Lecture 7: Medications in Diabetes

Question 1

How does LADA present?

Answer 1

It has the same pathogenesis as T1D but once it gets to pre-diabetes, it does not drop off to diabetes

Question 2

What are the types of antihyperglycemic agents for Type 2 diabetes?

Answer 2

1. Metformin (AMPK, acts on liver and muscle, decrease glucose production and increase glucose uptake)
2. Sulfonylureas (inhibits K channel in B cell)
3. Thiazolidinediones (PPARgamma, sensitizes tissues to insulin, upregulate GLUT4)
4. Meglitinides/glinides (inhibits K channel in B cell)
5. Glucosidase inhibitors (inhibits glucose uptake in gut)
6. Incretin Mimetics (GLP-1 agonist)
7. Incretin enhancers (DPP-4 inhibitors)
8. Insulin

Question 3

What are the principles of glucose lowering agents in type 2 diabetes?

Answer 3

1. Multiple drugs available, each with tissue specific action
2. All of these drugs, except insulin, are used for type 2 diabetes ONLY
3. All are contraindicated in pregnancy except for Glyburide (sulfonylurea) and metformin
4. Can be used in any combination except sulfonylureas should not be used with meglitinides
5. Metformin is generally first drug of choice
6. Can start with multiple classes of drugs

Question 4

What is the first drug of choice?

Answer 4

Metformin

Question 5

What are the two type 2 diabetes drugs that are NOT contraindicated in pregnancy?

Answer 5

1. Glyburide (sulfonylurea)

2. Metformin

Question 6

What are the two drugs that cannot be used in combination with one another?

Answer 6

1. Sulfonylureas + Meglitinides (because they have the same fucking MoA)

Question 7

What is the MOA of metformin (a biguanide drug)?

Answer 7

Works at the liver
Try to prevent production of glucose from liver
Activation/phosphorylation of AMPK (amp-activated protein kinase)
Funciton:
1. increase muscle glucose transport
2. decrease hepatic glucose production 
3. sensitizes insulin
4. reduces glycogenolysis
5. Reduces triglycerides

Question 8

What are the characteristics of metformin?

Answer 8

1. improves pre-meal glucose with MODEST effect on post-prandial glucose
2. Weight neutral but can induce weight loss
3. NOT metabolized so can accumulate in patient if there is renal insufficiency
4. Lowers A1c as much as 2%
   
   • the higher the A1c, the greater the efficacy of the drug

Question 9

What are the side effects of metformin? Contraindications?

Answer 9

Side effects: nausea, anorexia, diarrhea, lactic acidosis
Contraindications: prone to metabolic acidosis, hypoxic states, renal failure, cardiac ischemia
REQUIRES INSULIN FOR ACTION

Question 10

What are the goals of treatments?

Answer 10

1. Weight loss/neutral
2. no hypoglycemia
3. frequency of administration
4. oral pill vs. injectable

Question 11

What are side effects of treatment?

Answer 11

1. weight gain
2. fluid retention
3. hypoglycemia
4. frequency of delivery
5. injectable

Question 12

Is metformin used for pre-diabetics?

Answer 12

No because lifestyle changes do a lot more than for metformin

Question 13

What are the types of insulin secretagogues?

Answer 13

1. Sulfonylureas

2. Meglitinides/Glinides

Question 14

What is sulfonylurea?

Answer 14

An insulin secretagogue

Question 15

What is meglitinides/glinides?

Answer 15

An insulin secretagogues

Induces insulin release

Question 16

What is the MOA of sulfonylurea?

Answer 16

Binds to the sulfonyl receptor in Beta cell resulting in INHIBITION of ATP-dependent potassium channels, leads to depolarization of Calcium channel that leads to insulin secretory granule secretion
Stimulates pancreatic insulin secretion for 12-24 hours
Long acting

Question 17

What are the characteristics of sulfonylureas?

Answer 17

Has an immediate effect on pre-meal glucose
Metabolized in liver
Contraindication: T1DM, DKA, sulfa allergy
Adverse effects: hypoglycemia, WEIGHT GAIN, hunger
Lowers HbA1c up to 1.5%

Question 18

What is the MOA of meglitinides/glinides?

Answer 18

Stimulates insulin release by regulating (inhibiting) ATP-sensitive K+ channels on Beta cells
Stimulates pancreatic insulin secretion for 3-4 hours
Short acting

Question 19

What are the characteristics of meglitinides/glinides?

Answer 19

FAST ONSET
Side effects: low glucose 2-4 hours after meal, WEIGHT GAIN, patient compliance
Contraindications: T1DM, liver failure, DKA, sulfa allergy
Metabolism: hepatic by cytochrome P 450 enzyme system
Lowers A1c by 0.4%
Disadvantage is patient compliance because you have to take so many fucking pills!

Question 20

What is the MOA of thiazolidinediones?

Answer 20

Binds to nuclear PPAR(gamma) receptor causing increased transcription of GLUT 4 transporter
Action: DECREASES peripheral INSULIN RESISTANCE in skeletal muscle, adipose tissue, liver
Because more GLUT4 transporters are recruited
Works on
i. skeletal muscle
ii. adipose tissue
iii. liver

Question 21

What are the characteristics of thiazolidinediones?

Answer 21

Effects = lowers pre-meal and post-meal glucose
Pill by mouth once or twice daily
Side effects: WEIGHT GAIN, hepatocellular injury
Contraindications: active liver disease, heart failure, renal insufficiency
Reduces plasma triglycerides but increases LDL
SLOW motherfucking onset
DOES NOT INDUCE LOW BLOOD GLUCOSE
Lowers A1c up to 1.8%

Question 22

What is the MOA of alpha-glucosidase inhibitors?

Answer 22

Competitively inhibit the ability of enzymes in the small intestinal brush border to breakdown oligosaccharides and disaccharides into monosaccharides
Action: Delays GUT carb absorption, increases GLP-1
DECREASES GLUCOSE ABSORPTION IN GUT

Question 23

What are the key characteristics of alpha-glucosidase?

Answer 23

Post-prandial glucose only
Pill taken with meals
Side effects: Flatulence, abdominal bloating
Contraindications: GI disorders, esp in inflammatory bowel disease
Does not induce low glucose (because it just doesn’t allow glucose to get in in the first place)
Lowers A1c by 0.4%

Question 24

What T2D drug makes you fart?

Answer 24

Alpha-glucosidase

Ben Franklin

Question 25

What are exenatide and liraglutide? MOA?

Answer 25

GLP-1 agonists
Same actions as GLP-1
Synthetic verison of exendin 4, a protein found in the saliva of the GILA MONSTER

Question 26

What are the key characteristics of exenatide and liraglutide (GLP-1 agonists)?

Answer 26

Increased insulin
Lower glucagon
Slow gut motility
Induces satiety

Question 27

What is DPP-4?

Answer 27

Dipeptidyl peptidase-4

- uibiquitous serine protease
- cleaves N-terminal dipeptide
- inactivates GLP in 1 minute and GIP in 7 min

Question 28

What is the MOA of DPP-IV inhibitors

Answer 28

Action: increases duration of action of GLP-1 (prevents its breakdown)
Prevents dipeptidyl peptidase-4 with 80% inhibition at 24 hours

Question 29

What are the characteristics of DPP-IV inhibitors?

Answer 29

IMMEDIATE effect mostly on post-meal glucose
Not metabolized, excreted unchanged through kidneys
PO once daily
NO contraindications
Adverse effects = GI
Does not induce hypoglycemia
A1c lower bye 0.7%

Question 30

What is the MOA of Canagliflozin (SGLT2 inhibitor)?

Answer 30

Inhibits SGLT2
SGLT2 mediates glucose reabsorption in the kidney in the proximal tubule (lumen)
Allows you to secrete all your glucose without reabsorbing it

Question 31

What are the key characteristics of Canagliflozin?

Answer 31

1. Cotnraindications: ESRD, renal impairment
2. Side effects: vulvovaginal candidiasis, vulvovaginal mycotic infection, UTI, polyuria
3. lowers A1c by 0.7%
4. Weight loss of 2.2%

Question 32

What are the drugs that increase weight gain?

Answer 32

1. Sulfonylurea
2. Meglitinides
3. thiazolidinediones

Question 33

What are the drugs that cause weight loss or is neutral?

Answer 33

1. Metformin
2. Exenatide (GLP-1 agonist)
3. Incretin enhancers (DPP-IV antagonist)
4. alpha-glucosidase

Question 34

What are the initial therapies for T2D?

Answer 34

1. Lifestyle changes

2. Metformin

Question 35

What drugs have GI side effects?

Answer 35

1. Metformin
2. A-glucosidase
3. incretin enhancers
4. Exenatide (GLP-1 agonist)