Day 3: GLP-1 Receptor Agonists and Basal Insulin – Study Guide

Required Readings:
1. Pharmacotherapy: A Pathophysiologic Approach (12 th Edition) – NONE, below guide is adapted
from this chapter
2. Dr. Diez’s/Dr. Wells’ - GLP-1 Agonist slides
3. Dr. Diez’s/Dr. Wells’ Basal Insulin Therapy slides
4. Dr. Diez’s U-500 comparison/conversion chart

Supplemental Reading:
1. Figure 9.3 – ADA Standards of Care – Pharmacologic Approach

The following study guide has been adapted from the 12th Edition of DiPiro, Chapter 94.
Please utilize this study guide and the required slide decks above.

INCRETIN MIMETICS
(Glucagon-like peptide-1 Receptor Agonists) (GLP-1RA)

 KNOW - 4 Mechanisms of action:

1. Stimulate insulin release from β-cells in glucose-dependent manner

2. Suppress glucagon secretion to decrease hepatic glucose production
3. Suppress appetite peripherally by delaying gastric emptying to promote satiety and
decrease postprandial glucose spikes
4. Suppress appetite centrally by suppressing appetite pathways in hypothalamus

 KNOW - Combo Therapy: DPP-4 inhibitors (from day 2) do NOT provide added glycemic
benefit when combined with GLP-1 agents due to similar mechanisms of action. Patients
should NOT be on both classes of medications.

 KNOW - Common Side Effects (dose-related): Nausea, vomiting, constipation, diarrhea are the
most common (and largely due to delayed gastric emptying component of mechanism of
action). (see Dr. Diez’s/Dr. Wells’ slides for more details)

 KNOW - Hypoglycemia: rare as monotherapy (please note if GLP-1RA is combined with

sulfonylurea or insulin – there is an increased risk)

Dr. Diez/Dr. Wells - Caution use in: Patients with gastroparesis or Irritable Bowel Syndrome (IBS)
 KNOW - A1c Lowering: Understand GLP-1RA typically lower A1C by ~1 to 2%.
For purposes of the exam, know which agents (at max dose) are:
 Modest - with A1c lowering ~1 to 1.5%
 High - with A1c lowering ~1.8 -2.1% (see chart below)

 KNOW - Glycemic Impact: Daily GLP-1RA agents affect PPG more than FPG while weekly GLP-
1RA agents mainly lower FPG with little effect on PPG.

KNOW - Table below: (except - Byetta included for reference/not testable; as it is rarely used)
GLP-1 Brand Name Initial Frequency A1c Max Renal
agonist Dose Lowering Dose/ Dosing
at Max Frequency
Dose
Byetta 5 mcg BID 0.9% 10 mcg Avoid if CrCl < 30
Caution use: CrCl 30-50
Exenatide
Bydureon BCise 2 mg Weekly ~1.5% 2 mg Avoid if eGFR < 45

Liraglutide Victoza 0.6 mg* Once Daily 1.1% 1.8 mg

Dulaglutide Trulicity 0.75 mg Weekly ~1.9% 4.5 mg No renal dosing required
Semaglutide Ozempic 0.25 mg* Weekly 2.1% 2 mg
Semaglutide Rybelsus 3 mg* Once Daily 1.4% 14 mg
ORAL
* Start at this dose for tolerability and to minimize side effects during titration. KNOW: NOT a therapeutic dose -
Counsel patients!

 KNOW - Drug selection based on formulation: Bydureon BCise© (exenatide) and Trulicity©
(dulaglutide) are autoinjectors. These are good options for patients that are needle phobic and
with limited dexterity but be mindful that Bydureon BCise© has the highest rate of injection
site reactions. (see Dr. Diez’s/Dr. Wells’ slides for more details)

 KNOW – CV Outcomes: Liraglutide, dulaglutide, and semaglutide (injection ONLY) have proven
cardiovascular protective benefits – MORE to come on this on Day 5. (see Dr. Diez’s/Dr. Wells’
GLP-1RA slides for more details – Look for “**” at bottom of slide with GLP-1RA chart)

 KNOW - Rare incidence - Pancreatitis: Reported in clinical trials at a low incidence. No causality
has ever been proven. However, all patients should be screened for history of pancreatitis or
high risk factors (per Dr. Diez/Dr. Wells: TGs >800- 1000, or alcohol abuse) prior to initiation.
Per package labeling: Consider other anti-DM therapy if history of pancreatitis. (see Dr.
Diez’s/Dr. Wells’ slides for more details)

 KNOW GLP-1RA CONTRAINDICATION/Black Box Warning - Rare incidence - Medullary

Thyroid Carcinoma or Multiple Endocrine Neoplasia Type-2: in patients with a history;
 warning is based off rodent data that showed increased risk of thyroid c-cell tumors. Human
studies have not reproduced this finding. Patients should be asked regarding personal/family
history prior to initiation. (see Dr. Diez’s/Dr. Wells’ slides for more details)

LONG ACTING INSULIN (Basal Insulins)

 Understand - Mechanism of Action: The liver, even during fasting, continuously performs
glycogenolysis and gluconeogenesis sending glucose into the blood to feed peripheral tissues.
Long acting insulins diffuse from a subcutaneous depot at a slow, constant rate over a long
duration. The continuous diffusion of basal insulin into the blood matches the continuous
production of glucose by the liver and prevents blood sugars from rising throughout the day.

NOT TESTABLE: First patient was treated with insulin in 1922 and Nobel Prize was awarded in
1923 for its discovery to Frederick Banting and John Macleod. First humanized insulin was
produced in 1982. Prior to this, it was extracted from cows or pigs and had much higher rates of
allergic and injection site reactions.

REMINDER: Basal insulin is required in all patients with type 1 diabetes, even if they are not
eating.

NOT TESTABLE: The modern treatment approach in Type 1 Diabetes uses insulin pumps to
continuously diffuse short acting insulin microdoses instead of basal insulin. The pump gives
additional, bolus doses to cover meals.

 KNOW - Pharmacokinetics: Absorption of insulin from subcutaneous depot is dependent on

several factors, below are important factors for consideration in patient counseling:

Factors Clinical Pearls

Blood Increased absorption: if area of injection site is rubbed; skin temperature is
flow increased; exercise of muscles near injection site
Site of Most rapid absorption from abdominal fat, and slower from posterior of upper
Injection arms/lateral thigh.
Why is abdominal the best? Offers MOST consistent absorption

 KNOW - A1c Lowering: Unlimited A1C lowering potential and are the strongest glucose
lowering agent. In practice A1C lowering will be limited by a patient’s behaviors.

 KNOW - Initial Insulin in Type 2: Basal insulin is usually started in type 2 diabetes before short
acting insulin (discussed day 4) because it is easier for patients to manage and has a lower rate
of hypoglycemia.
 KNOW: Names, dosage strengths and pharmacokinetics of basal insulins.
Generic Name Brand Names Dose Forms Dose Strengths Peak Duration
 Intermediate acting
Regular Human Insulin Humulin R U-500 Vial, pen 500 units/mL 4-8h 13 - 24 h
Neutral Protamine Humulin N, Novolin N, Vial, pen 100 units/mL 4 - 10 h 10 - 24 h
Hagedorn (NPH)* Reli-On N
Detemir Levemir Vial, pen 100 units/mL 6 - 14 h 16 - 20 h
Long acting
Glargine Lantus, Basaglar, Vial, pen 100 units/mL None 20-24 h
Semglee
Glargine Toujeo Pen U-300 units/mL None 36 h
Ultra-long acting
Degludec Tresiba Vial, pen 100 units/mL None 42 h
200 units/mL
* NPH is the ONLY insulin not clear in appearance. It is conjugated to protamine and has a milky white/cloudy
appearance

NOTE: See Dr. Diez’s/Dr. Wells’ Basal Insulin Therapy slides for: Common side effects, dosing,
clinical pearls and pen examples

NOTE: While the above kinetics are generally what to expect, every patient will have different
kinetics dependent on where they inject, body composition, technique, diet, and exercise.
Individualize care for each patient as they will all be different.

 KNOW - Insulin Metabolism: ~20% of insulin metabolized is via the kidney. Thus in patients
with end-stage renal disease, insulin is known to have a longer duration of action, thus patients
often require LOWER insulin doses.

IMPORTANT FOR AWARENESS/future practice: Medication errors between regular &

protamine Hagedorn (NPH) insulins are common - due to similar names. Now, there are also
multiple concentrations for basal insulins (U-100, U-200, U-300, U-500) - this can lead to errors
with deadly consequences. As a pharmacist, you are chiefly responsible for preventing errors.

 KNOW - Insulin Storage:

1. Always store unopened insulin vials and pens in the refrigerator (ideally 2°C to 8°C).
Insulin should NEVER be frozen (ie, in Michigan - if left in a car during winter - no good).
2. Opened insulin products in current use should be stored at room temperature. Storing
them in the refrigerator does NOT prolong their stability or expiration.
3. Most insulins expire 28 days after being opened. Some last 42 days, check package
inserts if unsure.
4. Before use, patients should visually inspect insulin for irregularities (clumps or
cloudiness, if not NPH).

U-500 INSULIN
UNDERSTAND that U-500 insulin is FIVE TIMES as concentrated as U-100 insulin

 KNOW - Dosing Frequency: Dosed 2-3 times daily

 KNOW - Safe Prescribing Practice: The dose of U-500 should be expressed as the dose (via U-
500 concentration) AND dose via syringe dose (ie, mLs if via tuberculin syringe or units if via U-
100 syringe)

 UNDERSTAND NEED for special dosing syringe:

a. U-500 insulin vial should be dispensed with U-500 insulin syringe or (if unavailable), a
tuberculin syringe. Standard insulin syringes are designed for U-100 insulin with
markings to reflect this so using them with U-500 insulin will cause 5-fold overdosing.

1. Practice: How do you convert dose expressed as units of U-500 to a dose in mL to be drawn up
in tuberculin syringe? Let’s say prescription read U-500: Give 180 units TID

2. Practice: How do you convert dose expressed as units of U-500 to a dose in that can be drawn
up in a U-100 syringe? Let’s say prescription read U-500: Give 165 units TID

NOTE: Insulin is one of the highest risk drug classes and biggest sources of medication errors
locally, nationally, and globally. Every year, numerous people die or are hospitalized for severe
hypoglycemia due to mix-ups in dose strength, insulin product, use of incorrect syringe, or
mismatch of activity with pharmacokinetics. Always be diligent to prevent medication errors.

 Incorrectly dosing U-500 insulin can lead to severe hypoglycemia or death. It happens multiple
times unfortunately at hospitals and pharmacies around this country, and here, every year.
Always be diligent to prevent medication errors.