Lecture 13 / 14: Antidiabetic Agents Flashcards
Name the following Insulin and Insulin analogs:
* Rapid-acting (1)
* Intermediate-acting (1)
* Long-acting (3)
Rapid-Acting: Regular Insulin
Intermediate Acting: NPH Insulin
Long-Acting: Insulin glargine, Insulin detemir, Insulin degludec
What are the two classes of Liver, Muscle and Adipose Agents, and the one drug in each class?
- Biguanides: Metformin
- Thiazolidinediones: Pioglitazone
2 Classes of Enhanced B-cell Insulin Release? Drugs in each class?
- Sulfonylureas:
1. Glyburide
2. Glipizide
3. Glimepiride - Meglitinides:
1. Repaglinide
2 classes of drugs that Mimic or Prolong Gut Hormone Effects on B-cells?
3 drugs in each class?
- Glucagon-Like Peptide-1 Receptor Agonists:
1. Exenatide
2. Liraglutide
3. Dulaglutide - Dipeptidyl Peptidase-4 Inhibitors:
1. Sitagliptin
2. Saxagliptin
3. Linagliptin
Drugs that enhance renal excretion of glucose (3)
Sodium-Glucose Co-Transporter 2 Inhibitors
agliflozin ending
1. Canaglifozin
2. Dapaglifozin
3. Empaglifozin
What disease can inhibit metformin drug therapy?
Chronic Kidney Disease
What drugs can preserve kidney function in T2DM patients?
ACE inhibitors or angiotensin II receptor blockers (ARB)
Describe structure of insulin, the drug
chains, T1/2, metabolism / elimination
- 51 amino acid protein arranged in two chains (A and B; orange color); proinsulin is insulin with C peptide (green)
- T1/2 = 3-5 min (little to no albumin binding)
- 60% cleared in liver / 35-40% cleared in kidneys
What are the 2 therapeutic approaches for T2DM?
- Education
- Medications
What is the education provided to T2DM patients? Explain effects of bodyweight reduction on diabetes risk.
- proper diet, adequate exercise, smoking cessation
- If bodyweight reduced by 5-10% then risk of type II diabetes is reduced by 58%.
Diabetes medication for patients with NO underlying conditions?
Metformin
Medications for patients with NO underlying conditions: Additional med. if greater decrease in blood glucose is needed than on metformin alone?
Metformin + sulfonylurea
Medications for patients with NO underlying conditions: Greater glucose decrease than with metformin + sulfonylurea?
Metformin + sulfonylurea + insulin (or others)
Others:
* Dipeptidyl Peptidase-4 Inhibitor
* Glucagon-Like Peptide -1 Receptor Agonists
* Sodium-Glucose Co-Transporter 2 Inhibitors
What drugs to use for T2DM patients WITH atherosclerosis and cardiovascular disease
- Use glucagon-like peptide -1 receptor agonists; e.g. liraglutide, dulaglutide
- Increased weight loss with these drugs; helpful for these patients
Drugs for patients with T2DM patients WITH renal impairment or CKD. What else may be needed?
- Use sodium-glucose co transporter 2 (SGLT2) inhibitors; e.g. empagliflozin, canagliflozin, dapagliflozin
- Reduces progression of CKD
- SGLT2 inhibitors have less glycemic effect so additional medications may be needed
Insulin Therapy: Mechanism of Action
– binds to specific insulin receptors; overall effect is to
decrease blood levels of glucose and other nutrients (e.g. amino acids)
Insulin MOA in Liver?
Inhibit gluconeogenesis, inhibit conversion of amino acids to glucose/keto acids, promote glucose storage as glycogen
Insulin MOA in Muscle?
Banned substance?
- Increase: protein synthesis, transport amino acids and glucose, muscle growth. ** Insulin is a banned
substance according to World Anti-Doping Agency (not allowed in or out of competition)
Insulin MOA in Adipose tissue?
Increase storage of triglycerides, increase uptake of blood glucose
Side effects of insulin therapy?
blood sugar, weight, cancer, allergy, immune response
- Hypoglycemia
- Weight gain - not ideal (90% of T2DM patients are obese / overweight)
- Possible increased cancer BUT confounding variables due to obese patients at higher risk of cancer anyway
- Insulin allergy - rare; local or systemic urticarial, very rare: anaphylaxis
- Immune Insulin resistance - IgG antibodies against insulin (dosage increase needed)
Symptoms of hypoglycemia due to insulin? When is it most prevalent?
hunger, headache, tremors, weakness, sweating,
seizures
can be especially prevalent at night while sleeping
Why does insulin given subcutaneously work more slowly than endogenous insulin secreted by the pancreas?
- Tendency of reg. insulin to form non-covalent hexamers in solution
- Breakdown of hexamers to monomers requires time
Which 3 insulin analogs more readily form monomers in solution? How does this affect speed of action?
Aspart, glulisine and lispro
velocity of action closer to meal-induced peak of pancreatic insulin
What is only insulin suitable for intravenous use?
- Regular insulin (Humulin R and Novolin R)—a clear solution of human sequence insulin
What is the intermediate acting preparation? Why is it longer acting?
NPH Insulin
Human sequence insulin aggregated w/ protamine and zinc
The time involved in breaking down these aggregates causes the delayed, longer time course of NPH versus regular insulin
What is mechanism for longer acting insulin glargine?
Solubility at pH
Amino acids added that alter solubility, making it less so.
This insulin is soluble at pH 4 but poorly soluble at pH 7.
When injected subcutaneously, insulin glargine forms a fine precipitant in the interstitial fluids
Mechanism for long acting insulin detemir
Long-acting due to self-association at subcutaneous
injection site and by binding to albumin in the blood stream
Mechanism for long acting insulin degludec?
Long-acting due to self association at subcutaneous injection site and by binding to albumin in the blood stream
Why are multiple shots of a combo of intermediate or long acting, and short acting insulin administered?
What do short and longer acting insulins mimic?
- to mimic the profile of insulin levels found in non-diabetics
- Intermediate- and long-acting insulins are given to mimic 24-hour basal insulin secretion.
- Short-acting insulins are given preprandial to mimic nutrient-stimulated insulin secretion
Main 3 goals of insulin therapy? Do all patients achieve this?
fasting / post prandial / A1C
- Fasting and preprandial blood glucose level of 70-130 mg/dL
- Post-prandial blood glucose level two hours after meal of less than 180 mg/dL
- Hemoglobin A1C (HbA1C) less than 7% (associated with a decreased risk of long-term complications)
- Caveats: not all patients achieve these goals (hypoglycemia, cognition, age
What is first line drug therapy for T2DM?
Metformin
4th most prescribed drug in US
Metformin and hypoglycemia and weight gain?
Unlike insulin, it does not cause hypoglycemia and is termed an
“euglycemic” agent
also it does not cause weight gain; (insulin and sulfonylureas can cause weight gain)
Metformin: Metabolism and pharmacokinetics
t1/2, dose, binding , metabolism, excretion, use w/ caution w/ who?
- T1/2 1.5 to 3 hours
- max dosing is 850mg 3X per day 2.55 grams/day!
- Not bound to plasma proteins
- Not metabolized
- 100% excreted by kidneys as an active compound
- Use with caution in patients with decreased GFR (e.g. eGFR 45 – 30 mL/min per 1.73m2)
Metformin: MOA
- Inhibits liver gluconeogenesis
Metformin: Side Effects
GI, Metabolic, renal
- Gastrointestinal: Diarrhea nausea, vomitting and flatulence
- Infection (21%) - Lexicomp
- Metabolic acidosis – can be severe (Black Box warning), results from impaired hepatic metabolism of lactic acid; other biguanides in US were discontinued due to this effect
- For patients with renal impairment, metformin is not eliminated as expected resulting in increased risk of metabolic acidosis
What are the 3 sulfonylureas? When are they used? What do they require? What are the considered to be?
- Glyburide, Glimepiride, Glipizide
- Used in early stage T2DM
- require functioning beta cells;
- considered insulin secretagogues (promotes secretion)
Sulfonylureas: Metabolism and pharmacokinetics
metabolism, excretion, 2nd gen
metabolized in liver to inactive or partially active metabolites
excreted via kidney
second generation sulfonylureas also undergo bile excretion
Sulfonylureas: MOA
channel / cause
Glyburide, Glimepiride, Glipizide
Mechanism of action: bind to 140 kDa receptor associated with ATP-sensitive inward rectifying K+ channel
cause β-cell depolarization and insulin secret
Which sulfonylurea has shortest half life? When is it taken?
Glipizide – shortest half life (2 - 4hr); taken prior to individual meals
Sulfonylureas: Side Effects
- Hypoglycemia
- Weight gain may occur due to an increase in appetite
- A sulfur allergy may occur in susceptible patients
- Increased cardiovascular mortality in 1st generation sulfonylureas has been associated with long-term sulfonylurea treatment although other studies do not show this association
What class of drug is Repaglinide? How is it similar to sulfonylureas?
whats necessary / MOA?
Meglitinide
Similar to sulfonylureas in terms of:
* Require functioning pancreatic beta cells (T2DM patients) and is considered insulin secretagogue
* Mechanism of action: inhibit K+
ATP gated channels in pancreatic β-cells – depolarize cells
Repaglinide: Side effects
- Hypoglycemia
- No sulfur, so can be used in patients with sulfur or sulfonylurea allergies
What are the 3 Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists, and their MOA?
Exenatide, Liraglutide, Dulaglutide
MOA: GLP-1 receptor activation in pancreatic β-cells enhances or augments glucose stimulated insulin secretion (GSIS)
What is a positive side effect of GLP1 receptor agonists?
In CNS, GLP-1 produces the feeling of satiety. Reduced body weight is a positive side effect… great for T2DM patients; 4.5 lbs lost over placebo group
GLP-1 Receptor Agonists: Metabolism and Pharmacokinetics
route, metablisim enzyme, t1/2
Exenatide, Liraglutide, Dulaglutide
All drugs given by subcutaneous injection
metabolized in blood by dipeptidyl peptidase-4 (DPP-4)
half life widely varies 2.5 hours for exenatide to 5 days for dulaglutide
What is GLP-1 Agonist a derivative of? T1/2? Dose? Metabolism?
- Derivative of the exendin-4 peptide in Gila monster venom
- Short half life 2.5 hours; dosed 60 minutes before meal
- 53% homology with normal GLP-1
resists metabolism/degradation by DPP-4
GLP-1 agonists: Side effects
do they improve?
nausea (up to 28%), vomiting (up to 10%); 4% of patients
dropped out of a clinical study due to nausea
nausea goes away with continued drug use
What are the 3 Dipeptidyl Peptidase-4 (DPP-4) Inhibitors? Metabolism / pharmacokinetics?
route, t1/2,
Sitagliptin, Saxagliptin, Linagliptin
- Given by oral administration (p.o.)
- Metabolism and pharmacokinetics: half life 2 – 12 hours depending on drug
which is only DPP4 inhibitor that is eliminated by biliary secretion?
Linagliptin
Only DPP4 inhibitor that requires no dose adjustment for renal dysfunction or CKD?
Linagliptin
DPP4 inhibitors: MOA
Sitagliptin, Saxagliptin, Linagliptin
Mechanism of action: Inhibit DPP-4 activity which inhibits degradation of GLP-1
extending actions of GLP-1 on pancreatic β-cells
DPP4 Inhibitors: Side effects
increased risk of pancreatitis, can be severe
animal studies show DPP-4 inhibitors and GLP-1 agonists may increase risk of pancreatic cancer but no human data show increased risk.
3 Sodium-glucose Co-transporter 2 (SGLT-2) Inhibitors:
1. How much glucose is reabsorbed
2. How much do they lower A1C
3. What reduces efficacy
Canaglifozin, Dapaglifozin, Empaglifozin
- 90% of filtered glucose in glomerular filtrate is reabsorbed by SGLT-2
- SGLT-2 inhibitors can lower A1C levels by up to 1%; on par with DDP-4 but not as good as GLP-1 agonists
- Due to effects on kidney, efficacy is reduced in patients with CDK
SGLT-2 Inhibitors: Metabolism and Pharmacokinetics
route, metabolism
Canaglifozin, Dapaglifozin, Empaglifozin
* Given by oral administration
* Metabolism: mostly fecal elimination of active drug with some glucuronide conjugation and renal elimination of metabolites
SGLT2 Inhibitors: MOA
Canaglifozin, Dapaglifozin, Empaglifozin
MOA: Inhibit SGLT-2 in renal proximal tubules to reduce glucose reabsorption from glomerular filtrate in nephron
Increased excretion of glucose
SGLT2 Inhibitors: Side effects
: like GLP-1 agonists, reduced bodyweight – idea in T2DM patients
* For all: increased risk of genital or urinary tract infections (9%)
* **Canaglifozin: increased risk of bone fractures (30%), at least in one study **
* Ketoacidosis in insulin dependent type I or T2DM patients.
Why can SGLT2 inhibitors cause ketoacidosis?
Because blood glucose remains normal while taking SGLT-2 inhibitors so insulin is withheld resulting in diabetic ketoacidosis. 2017 FDA warning issued
2 alpha-glucosidase inhibitors: MOA and side effects (these are not bolded or even mentioned on drug list, but have some underlined areas in slides)
acarbose and miglitol
MOA: Delay digestion and absorption of ingested starches and disaccharides
Reduces postprandial glucose levels by 30-50%
NOT used often in US due to prominent side effects
related to GI; flatulence, diarrhea, and abdominal
pain/bloating due to fermentation of sugars in large
intestine
