Type 2 Diabetes and Drugs Flashcards
Which tissues/organs are affected in Type 2 diabetes?
Liver
—Hepatic glucose production increases
Pancreas
—Plasma glucagon secretion increases
Skeletal muscle
—Glucose utilization decreases
Adipose Tissue
—Lipolysis increases
What is Type 2 diabetes a combination of?
Insulin Secretion + Insulin Resistance
Which agents enhance insulin secretion?
(used for hypoglycemia)
-Sulfonylureas
(tolbutamide, tolazamide, chlorpropamide, glyburide, glipizide, glimepiride)
-Meglitinides
(nateglinide, repaglinide)
What is required for Type 2 diabetics to be able to use sulfonylureas?
-Must have functioning beta cells
What effects do sulfonylureas have on patients with Type 2 diabetes?
-Restore first phase insulin release
-Increase beta cell sensitivity to glucose
-Increase glucose stimulated insulin release
*Overall: increase insulin release
What needs to happen for insulin to be released from pancreatic beta cells? (High Glucose levels)
- Glucose is taken up into the cell by GLUT2 transporters
- Glucokinase phosphorylates glucose to G6P
- G6P is metabolized and ATP is created
- ATP binds to the K+ channel which CLOSES it
- This depolarizes the membrane and opens Ca2+ channels
- These Ca2+ channels release insulin
How do sulfonylureas work?
They bind to the sulfonylurea receptor found on K+ channels
–this inhibits the K+ channel from opening, ultimately depolarizing the membrane and opening Ca2+ channels so that insulin can be released
What happens to insulin release when there are LOW levels of glucose present?
No insulin is secreted
-Glucose is not brought into the pancreatic beta cells so there is more ADP than ATP
-ADP binds to the K+ channel and OPENS it
-This stabilizes the negative resting membrane potential and prevents Ca2+ channels from opening
Which is faster: Glucose or Tolbutamide?
Tolbutamide
-able to immediately bind to the K+ channel and depolarize the membrane
What are the first generation sulfonylureas?
Tolbutamide
Tolazamide
Chloropropamide
What are the second generation sulfonylureas?
Glipizide
Glyburide
Glimepiride
What is the most potent 1st generation sulfonylurea?
Chlorpropamide
What is the least potent 1st generation sulfonylurea?
Tolbutamide
How does the potency of first generation sulfonylureas compare to the potency of second generation sulfonylureas?
2nd generations are much more potent!
What are the two more potent 2nd generation sulfonylureas?
Glyburide and Glimepiride
What word-endings indicate that a drug is a sulfonylurea?
“amide” and “ide”
What form of insulin are 2nd generation sulfonylureas comparable to in terms of the duration they work in the body?
Long-lasting insulins
How do Meglitinides work?
Have the same mechanism of action as sulfonylureas
-Bind the K+ channel and prevent it from opening
What is the onset/duration of action of Meglitinides?
-Quick onset
-Short duration of action
When should Meglitinides be taken?
Before each meal
What form of insulin are Meglitinides comparable to?
Fast-Acting Insulins
How does the half-life of Nateglinide (Starlix) compare to that of Repaglinide (Prandin) and how does this affect the risk for hypoglycemia?
Nateglinide (Starlix) has a shorter half-life
*Less risk of hypoglycemia
Can Nateglinide (Starlix) be used with Metformin?
Yes
What are the possible adverse effects of sulfonylureas?
-Hypoglycemia
-Cardiovascular events + Mortality (some evidence)
-G.I. problems
-Weight Gain
-Secondary failures
Why are sulfonylureas prone to causing hypoglycemia?
They have a long half-life
Which sulfonylurea is most likely to cause hypoglycemia?
Glyburide
What are secondary failures and why can these occur with sulfonylureas?
When patients are on sulfonylureas for a long time, they can experience a decreasing ability to secrete insulin
*Patient will likely have to eventually go on insulin
-Caused by extra stress on the beta cells that reduces their functioning over time
What two drugs are the biggest concerns when taking sulfonylureas due to an interaction occurring?
-Alcohol
-High Dose Salicylates
**The drugs have their own hypoglycemic effects and therefore add onto the hypoglycemic effect of sulfonylureas
(Increase hypoglycemic effect)
Which drugs enhance the incretin effect?
GLP-1R Agonists
GLP-1 & GIP Dual Agonists
DPP-IV Inhibitors
Amylin Analogs
What is the incretin effect?
Oral glucose stimulates a larger insulin response than IV glucose
Where is GIP excreted from?
K cells of the duodenum
Where is GLP-1 excreted from?
L cells in the ileum
What is the result of GIP and GLP-1 release when they are able to stimulate beta cells in the pancreas?
-Increase insulin secretion
-Increase beta cell proliferation and protection from apoptosis
Demonstrate the incretin effect
What is the role of DPP-IV protease?
Degrades GIP and GLP-1
When are GIP and GLP-1 released from the intestines?
When blood glucose is elevated after a meal
Is the release of GLP-1 (stimulated insulin secretion) glucose dependent?
YES
What affect does GLP-1 have on the beta cells?
Increases their mass AND maintains their function
Does GLP-1 stimulate insulin secretion by itself?
NO
-amplifies the ability of glucose to stimulate insulin secretion
How does Type 2 Diabetes affect the Incretin Effect?
Incretin Effect is diminished
How does Type 2 diabetes affect GLP-1 levels?
GLP-1 levels are decreased
What are the two strategies to providing GLP-1 treatment in Type 2 diabetes?
1) Provide a long-lasting GLP-1 analog
2) Prevent degradation of endogenous GLP-1
What are the benefits of GLP-1 treatment?
-Reduce hyperglycemia (low risk of hypo)
-Weight loss
-Increase beta cell mass
What are the GLP-1R Agonists? (AKA GLP-1 Analogs)
-Exenatide
-Liraglutide
-Lixisenatide
-Dulaglutide
-Semaglutide
What word-ending indicates that a drug is a GLP-1R agonist?
“tide” some exceptions
What warnings are associated with ALL GLP-1R Agonists (GLP-1 Analogs)?
-Nausea and Vomiting
-Pancreatitis
-Risk of thyroid c-cell tumors (monitor calcitonin levels)
Contraindicated in patients with family history of medullary thyroid cancer
What is Exenatide and how does it work?
GLP-1R Agonist (GLP-1 Analog)
-Is a 39 amino acid peptide originating from Gila Monster saliva
*Activates GLP-1 Receptor
*Enhances 1st phase secretion
*Has a longer half-life than GLP-1 (resistant to degredation)
How often is Exenatide admistered?
-Twice daily injection
-Once weekly injection
Can Exenatide be co-administered with other medications?
YES:
-Metformin
-TzDs
-Sulfonylureas
What is Liraglutide (Victoza) and what is its structure?
GLP-1R Agonist (GLP-1 Analog)
*Most other GLP-1 analog drugs have an alanine that is changed so that they cannot be cleaved by DPP-IV
*Liraglutide does not have this change!!!!!
**Instead: has a fatty acid bound to it to enhance its duration of action by binding to serum albumin
How often is Liraglutide injected?
daily
Can Liraglutide (Victoza) be co-administered with other medications?
YES:
-Metformin
-TzDs
-Sulfonylureas
What is Dulaglutide (Trulicity) and what is its structure?
GLP-1R Agonist (GLP-1 Analog)
-The Alanines(A) in the molecule are changed to Valines(V) to prevent inactivation by DPP-IV
How often is Dulaglutide (Trulicity) injected?
Once weekly
Very potent
How are GLP-1 agonist peptides released from the IgG Fc domain?
They are released slowly by the reduction of disulfide bonds in their linker region
What is Lixisenatide (Adlyxin) and what is its structure?
GLP-1R Agonist (GLP-1 Analog)
Has the structure of exenatide but with a polylysine tail!
*IS NOT A GLP-1 SEQUENCE DERIVATIVE
How often is Lixisenatide (Adlyxin) injected?
Once daily before breakfast
What is Soliqua?
A combination product with Glargine and Lixisenatide
(Basal Insulin and GLP-1 Receptor Agonist)
What is Semaglutide (Ozempic) and what is its structure?
GLP-1R Agonist (GLP-1 Analog)
-The alanine in the molecule is replaced with a 2-Aminoisobutyrate (a non-natural amino acid)
–This helps the molecule to not be cleaved by DPP-IV
How often is Semaglutide (Ozempic) injected?
Once weekly
*Very potent
–Bound to serum albumin so it has a long half-life
What is the FIRST AND ONLY orally available GLP-1 Receptor Agonist?
Rybelsus (oral semaglutide)
What is Xultophy?
A combination product with Degludec and Liraglutide
(Insulin and GLP-1 Receptor Agonist)
What two pathways do GIP and GLP-1 stimulate?
cAMP Pathway
ERK1/2 Pathway
What is Mounjaro (Tirzepatide)?
Full GIP Receptor Agonist
+
Biased GLP-1 Receptor
**Dual agonist, activates both receptors!
Does Mounjaro (Tirzepatide) prefer to couple to cAMP or Beta-arrestin?
cAMP
**preferring beta-arrestin would lead to desensitization of GLP-1 receptors
How does Mounjaro (Tirzepatide) work?
Reduces internalization (desensitization) of GLP-1 receptors to maintain the GLP-1 effect
How often is Mounjaro (tirzepatide) injected?
Once weekly
How does Mounjaro (Tirzepatide) effect A1C and Body Weight in comparison to GLP-1 receptor agonists?
Mounjaro lowers A1C and bodyweight MORE EFFECTIVELY than GLP-1 receptor agonists
What effect does inhibition of DPP-4 have on release of the incretin hormones?
Both GLP-1 and GIP have a GREATER release
What are the 4 Inhibitors of DPP-4?
-Sitagliptin (Januvia)
-Saxagliptin (Onglyza)
-Linagliptin (Tradjenta)
-Alogliptin (Nesina)
What word ending indicates that a drug is a DPP-4 Inhibitor?
“gliptin”
What is the mechanism of action of DPP-4 inhibitors?
Enhance the actions of endogenous GLP-1
-Reduce hyperglycemia
-Reduce A1C
How do DDP-4 inhibitors work?
They bind in the active site of DDP-4 and block the incretins from being able to access it
How often are DDP-4 inhibitors dosed?
Once daily
**orally
What treatment is available for people who are NOT OPEN TO INJECTIONS?
DDP-4 inhibitors
(oral)
Why is there a low risk of hypoglycemia associated with DDP-4 Inhibitors?
They work through the incretin effect and do not directly stimulate insulin secretion
Are DDP-4 inhibitors affected by weight?
NO, they are weight-neutral
Which DPP-4 Inhibitors are Not Extensively Metabolized, and Excreted in the Urine (by the kidney)?
Januvia
Nesina
Which DPP-4 Inhibitor is Not Extensively Metabolized, and Excreted in Feces (by the liver)?
Tradjenta
Which DPP-4 Inhibitor is a CYP3A4/5 substrate and has a major metabolite that is active?
(also secreted in the urine by the kidney)
Onglyza
What are the 3 severe side effects associated with DPP-4 Inhibitors?
-Pancreatitis
-Joint Pain
-Heart Failure
*also associated with GLP-1 agonists
What alternative cell is DPP-4 found on besides endothelial cells, and what side effect can this cause?
Immune Cells
-Can cause reduced white blood cell counts which can lead to infections
-Potential risk of cancer
What is an alternative strategy to using DPP-4 inhibitors?
Positive Allosteric Modulators
–Make the low concentrations of incretins present more effective
What is the one Amylin Analog available?
Pramlinitide (Symlin)
What are the effects of Pramlinitide (Symlin)?
-Slows gastric emptying
-Decreases food intake
-Inhibits glucagon secretion
What effect does Pramlinitide (Symlin) have on postprandial blood glucose levels?
It blunts these levels
How is Pramlinitide (Symlin) administered?
In conjunction with insulin
*For use in both Type 1 and Type 2 diabetes
Which agents can reduce glucose absorption or increase glucose excretion?
alpha-glucosidase inhibitors
SGLT2 inhibitors
What are the alpha-glucosidase inhibitors?
Acarbose
Miglitol
What is the mechanism of action of alpha-glucosidase inhibitors?
Inhibit alpha-glucosidase which cleaves disaccharides into monosaccharides so that they are absorbed better (do not want this)
*decreases carbohydrate absorption from the intestine
How does the absorption of the two alpha-glucosidase inhibitors differ?
Acarbose: minimally absorbed (stays in GI tract)
Miglitol: completely absorbed (gets into bloodstream)
What are the adverse affects of alpha-Glucosidase Inhibitors?
GI affects (diarrhea, nausea, flatulence)
Acarbose: liver damage
Why are alpha-glucosidase inhibitors not the 1st choice of drug to use?
They can raise the A1C
What are the SGLT2 Inhibitors?
Canagliflozin
Empagliflozin
Dapagliflozin
Ertugliflozin
What word ending indicated that a drug s an SGLT2 Inhibitor?
“gliflozin”
How do SGLT2 inhibitors work?
Inhibit the Sodium Glucose coTransporter 2
–Decreases the threshold for glucose excretion in urine to reduce blood glucose levels
(more glucose excreted through urine)
What other substance besides glucose has increased excreted in the presence of SGLT2 Inhibitors?
Sodium
How are SGLT Inhibitors given?
Orally!
*Adjunct to diet + exercise
What are some benefits of using SGLT2 Inhibitors?
-Lower A1C
-Produce weight loss
What are some adverse effects of SGLT2 inhibitors?
-UTI’s and genital infections
-Increased urine flow depletion/hypotension
-Diabetic ketoacidosis (DKA)
Increased risk of lower limb amputation –Canagliflozin
When are SGLT2 Inhibitors Contraindicated?
-In patients with renal impairment
(this drug requires renal activity to work)
What agents reduce insulin resistance/lipotoxicity?
Biguanides
Thiazoladinediones
What is Metformin (Glucophage)?
Biguanide
-Antihyperglycemic agent
-Oral antidiabetic drug
*Does not stimulate insulin secretion, just targets the tissues that respond to insulin and increases their responsiveness
What is a benefit to using Metformin instead of older biguanides?
Lower risk for lactic acidosis
What are the advantages of using a biguanide instead of sulfonylureas?
-Rarely causes hypoglycemia
-Rarely causes weight gain
What is the mechanism of action for Metformin (Glucophage)?
Activates AMP-activated kinase (AMPK)
-increases sensitivity to insulin in liver, fat, and muscle
How is metformin dosed?
Three-times daily
**not very potent
How does metformin work in the liver?
-Works on complex 1 of the electron transport chain
-Inhibits ATP production and increases AMP
-AMP accumulates and inhibits Fructose- 1,6-bisphosphate in gluconeogenesis
-This reduces export of glucose by the liver
How does metformin work in the skeletal muscle?
-AMP accumulates during exercise and activates AMPK
-AMPK phosphorylates TBC1D1/4 which promotes GTPase activity of Rab
-Rab dissociates from GLUT4
-GLUT4 is translocated to the membrane
-GLUT 4 takes glucose out of the blood and brings it into the skeletal muscle
When is metformin contraindicated?
In disorders that increase the tendency for lactic acidosis
What vitamin has decreased absorption when a patient is taking metformin?
B-12
What effects does metformin have on the blood-lipid profile?
-Decreased serum triglycerides
-Decreased serum LDL
*reduces risk of cardiovascular effects
What is the first drug given to a patient diagnosed with Type 2 diabetes?
Metformin
What is the mechanism of action of thiazolidinediones?
Activate peroxisome proliferator-activated receptor gamma (PPARy)
–a transcription factor
-Decrease insulin resistance or improve target cell response
What is the main target of thiazolidinediones?
Adipocytes
-enhances free fatty uptake into fat to reduce serum levels
What are the two thiazolidinediones?
Rosiglitazone (Avandia) and Pioglitazone (Actos)
What word ending indicates that a drug is a thiazolidinedione?
“glitazone”
Why is thiazolidinedione prescribing limited?
They cause cardiovascular toxicities
What are the contraindications for thiazolidinediones?
Contraindicated in:
NYHA (advanced stage heart failure) Class III or IV
What is the function of Resistin, what are its levels in Type 2 diabetes, and what are its mRNA levels in response to thiazolidinediones?
Function: Stimulates glucose export by liver + causes insulin resistance
Levels in Type 2 Diabetics are: Elevated
mRNA levels in response to thiazolidinediones are: Decreased
What is the function of Adiponectin, what are its levels in Type 2 diabetes, and what are its mRNA levels in response to thiazolidinediones?
Function: Reduces blood glucose and insulin resistance
Levels in Type 2 Diabetics are: Decreased
mRNA levels in response to thiazolidinediones are: Increased
What is the function of TNFa, what are its levels in Type 2 diabetes, and what are its mRNA levels in response to thiazolidinediones?
Function: Stimulates lipolysis, stimulates insulin resistance
Levels in Type 2 Diabetics are: Increased
mRNA levels in response to thiazolidinediones are: Decreased
