Non-Insulin Diabetes Therapies Flashcards
2 ways that insulin leads to glucose homeostasis
- Liver - insulin suppresses glucose production
- Muscle - insulin increases glucose uptake
Note that the brain and the stomach are increasingly important in glucose homeostasis
Where do the non-insulin drugs act?
- Sulfonylureas - pancreas
- Incretin enhancers - brain; gut
- Thiazolidinediones - adipose tissue; muscle
- Metformin - liver
What is the action of sulfonylureas (Glyburide, glipizide, glimepiride)?
NOT glucose dependent at all (totally bypasses it)
close the ATP-sensitive K+ channels in the beta-cells, so that it bypasses the glucose requiring part –> depolarization of membrane –> intracellular flux of calcium –> release of insulin from granules
Pros and cons of sulfonylureas
Pros:
- Inexpensive
- Combos available with metformin and thiazolidinediones - may lead to better adherence
Cons:
- Weight gain
- Hypoglycemia
- Loses effectiveness with longer duration of diabetes - depends upon how responsive your pancreatic beta cells are (so less beta cells = less function)
Metformin
Biguanide: potentiates the suppressive effect of insulin on hepatic glucose production. Does NOT stimulate insulin secretion OR increase circulating insulin levels
Lowers hepatic output
Note: phenformin was pulled off the market because of lactic acidosis
Metformin pros and cons
Pros: 1. MoA 2. No hypoglycemia 3. Inexpensive 4. No wt gain 5. Combo pills First line therapy
Cons:
- Side effects: GI (if start with 1/4 dose, then see less side effects, titrate up)
- Risk of lactic acidosis in the following settings:
- Contrast media
- CHF
- Renal insufficiency
TZDs MoA
Bind to the nuclear peroxisome proliferator-activated receptors (PPARs)
Increase insulin sensitivity - stimulation of adiponectin production
Pros and Cons of TZDs
Pros:
- MoA
- Promise of other beneficial effects
Cons:
- MAJOR side effect = worsening of CHF
- Expensive
- Bladder cancer risk with >1yr of pio treatment
- Fractures
How is the incretin effect changed in pts with diabetes
It is a lot smaller, don’t respond as much to either oral or IV glucose load
What are the 2 incretins?
GLP-1: effective for lowering glucose in diabetes
GIP
- Secreted by cells in GI tract
- Only done when glucose is high
Why can’t you use GLP-1 as a medication?
Rapidly inactivated (in minutes) in bloodstream by dipeptidyl peptidase IV (DPP-4), so you would have to keep infusing it continuously.
GLP-1 agonists
Pros:
- multiple MoA to lower postprandial glucose
- effects are glucose-dependent
- weight loss
Cons:
- SC injections (1 and done, no sliding scale)
- side effects (nausea)
- expensive ($200-400/mo)
Other things of note:
Suppress appetite and slow gastric emptying
DPP-4 inhibitor
Goal: make endogenous GLP-1 levels higher by preventing breakdown by DPP-4
Result: get increased half life of GLP-1 and GIP
Drugs: came out in 2006, are oral meds
Pros:
- Stimulation of insulin secretion by pancreas, suppression of glucagon usage postprandial
- Oral
- Qd
- Weight neutral
- Combo pill
Cons:
- Less potent (don’t lower glucose as much)
- Expensive ($200-400)
- Side effects (nausea, allergic rxns)
SGLT-2 inhibitors
SGLT-2 is present in the kidney, and normally helps with reabsorption of glucose in the kidney.
Inhibiting this lowers the renal threshold for glucose. (normally it is ~180)
Can still have glycosuria (peeing out glucose to blood sugar of 100)
Lose 300-400 calories that way
SGLT-2 inhibitors pros and cons
Pros:
- novel mechanism
- weight loss
- oral
- at least 1 available as combo
Cons:
- Increased risk for GU and UTI infection
- Increased risk for low K+
- Expensive
- Unknown long-term safety (Euglycemic DKA)
