Oral Hypoglycemics

Question 1

What is the main method of treatment for DM Type 2?

Answer 1

• ->Oral hypoglycemics!

- Stimulates Beta cells to release insulin

Question 2

Metformin:

Answer 2

The Gold Standard for Type 2 Diabetes (Biguanides)

-Good efficacy, low risk of hypoglycemia, no weight gain and relatively safe.

Question 3

Incretins

Answer 3

• Endogenous (exist within the body)

- Mediate communication between the gut and the brain (potential target for weight loss drugs)

Question 4

• Glucagon- like peptide (GLP-1)

- Glucose-depedent Insulinotropic Peptide (GIP)

Answer 4

Examples of Incretins

Question 5

What are the 2 variations of Incretins?

Answer 5

1. GLP-1 Agonists– Liraglutide

2. DPP-4 Inhibitors– Sitagliptin

Question 6

Explain the basic physiology behind Insulin Release from Pancreatic Beta Cells.

Answer 6

-Glucose enters the cell through GLUT 4 transporters, which is metabolized in the cell to increase ATP. This increase in ATP/ ADP ratio causes the closure of KATP channels, which causes the cell to depolarize. This allows Ca2+ to enter the cell through Ca2+ channels, leading to the exocytosis of insulin from secretory granules.

Question 7

How do Incretins block Insulin release from pancreatic beta cells?

Answer 7

Incertains augment glucose stimulated insulin release by blocking KATP channels, which makes receptors more receptive to physiological glucose levels.

-Incretins increase insulin secretion, inhibit glucagon secretion, delay gastric emptying and reduce appetite.

Question 8

How are GLP-1 agonists administered?

Answer 8

Subcutaneous Injection
*May have a more pronounced effect on the GI tract compared to GPP-4 inhibitors (may reduce gastric emptying to interfere with drugs needing rapid absorption)

Question 9

How are DPP-4 Inhibitors administered?

Answer 9

Oral Administration

Question 10

What are the main side effects of Incretins?

Answer 10

-Hypoglycemia: Less common than with insulin or insulin secretagogues

• Rare, but serious risk of Pancreatic Disease
• Pancreatitis (Cancer)

Question 11

Liraglutide:

Answer 11

GLP-1 agonist
-Side Effects:

• Gastrointestinal (N/V or constipation)
• Weight loss (approved as a weight loss drug)
• Increased risk at forming gallstones

Rare, but serious adverse effects include increased heart rate, arrhythmia and possible think with thyroid cancer.

Question 12

Sitaliptin:

Answer 12

DDP-4 Inhibitor
Side Effects:
-Gastrointestinal: GI side effects are less common compared to Liraglutide

• Increased Risk of Infection:
• Typically upper respiratory tract or urinary tract infections.

DPP-4 inhibitors play a direct role in the immune system (lymphocytes)

Question 13

Thiazolidinedione’s (TZD’s) aka “Glitazones”

Answer 13

• Peroxisome Proliferator Activated Receptor- gamma aka (PPAR-γ) agonist
• Regulate genes related to glucose and lipid metabolism
• Because they work on gene expression, TZD effects tend to be delayed.

Question 14

Mechanism of Action of Glitazones:

Answer 14

• Insulin sensitizers- increase the uptake of glucose
• TZD enhances the uptake of free fatty acids into adipose tissue.
• This leaves less FA’s available to enter other tissue.
• Higher tissue adipose levels tend to reduce the sensitivity to insulin.
• Reduces hepatic production of glucose (reduces gluconeogensis)
• Reduces TG’s (increases HDL-C)

CONSISTENT SAFETY ISSUES LIMIT THEIR USE

Question 15

Pioglitazone:

Answer 15

-Type of Thiazolidinedione

Side Effects:

• CV (heart failure)
• Edema
• Weight gain (Reduces Leptin Levels)
• Fractures (Especially in women, reduces bone density)

Question 16

Alpha- Glucoside Inhibitors (AGI’s) Mechanism of Action:

Answer 16

• ->Glucosidases break down carbohydrates into glucose.

- AGI’s inhibit the breakdown of carbs, preventing absorption.

Question 17

Acarbose:

Answer 17

-Alpha- glucoside inhibitor (AGI)
Side Effects:
GI: Bloating, diarrhea and pain
-Bacteria feed on undigested carbs, which release gas.

Low risk of Hypoglycemia
-If it occurs, need to administer glucose (sucrose won’t be absorbed)

Question 18

Sodium- Glucose Co Transporter 2 (SGLT-2) Inhibitors Mechanism of Action:

Answer 18

• Inhibit renal mechanism for reabsorbing glucose.
• In non-diabetic individuals, all filtered glucose is reabsorbed. 90% of glucose reabsorption occurs at the Proximal Tubule (PT).
• Inhibiting SGLT-2 reduces glucose reabsorption leading to osmotic diuresis, and reduces blood pressure.
• Also induces weight loss.
• May reduce BP (via osmotic diuresis)

Question 19

Empagliflozin:

Answer 19

• SGLT-2 inhibitor
• Act on the proximal tubule to inhibit the sodium- glucose co transporter.

Adverse Effects:
-Increased glucose in the nephron increases the risk of infections (UTI’s and Genital Infections)
-Dizziness and hypotension
(reduced blood volume due to the osmotic diuresis)
-Nausea
-Hyperkalemia

Rare, but serious diabetic ketoacidosis.

Question 20

What drug can be combined with essentially anything in treating DM Type 2?

Answer 20

Metformin (Biguanide)

*Benefit of combination includes it’s effect on weight gain.

Question 21

Adding 2 drugs that cause weight gain can lead to a NEUTRAL EFFECT on weight:

Answer 21

• Metformin + Insulin
• Metformin + Sulfonylurea

*These drugs, which increase risk of hypoglycemia, in combination actually REDUCE risk.

Question 22

Adding drugs that have a neutral effect or reduce weight can ENHANCE weight gain:

Answer 22

-Metformin + SGLT-2 Inhibitor + DPP-4 inhibitor

Question 23

Future Drugs to treat DM Type 2?

Answer 23

• Inhaled Insulin (Approved in the US)
• Powder Form (Inhaled through the mouth)

Issues:

• Cost: First device failed to catch on.
• Concerns over bronchospasm
• Patches (using micro needle technology)
• Stem cells (Islet cell transplants)