Oral medications and GLP-1 receptor agonists in treating T2DM Flashcards
What is the MOA of metformin (biguanide)?
Activates AMPK in hepatocytes and skeletal muscle which decreases ATP consuming reactions and increases ATP producing reactions= leads to increased insulin sensitivity
-In hepatocytes: decreases gluconeogenesis and decreases cholesterol, TG, and FAT synthesis
In skeletal muscle: increases GLUT4 translocation which leads to increased glucose uptake
What are the therapeutic effects of metformin?
- High efficacy (lowers a1c more than 1.5%)
- No hypoglycemia
- Lower plasma glucose leads to lower plasma insulin (beneficial for PCOS tx)
- Lowers LDL-C, TGs, and increases HDL-C
- Weight neutral/weight loss
What are adverse effects seen in metformin?
- GI issues- diarrhea, nausea, abdominal discomfort, metallic taste, decrease vit B12 absorption
- Lactic acidosis (rare)- more likely in pts with decreased kidney function, tissue hypoxia (from cardiopulmonary disease), liver toxicity, and excess alcohol use
What are important considerations of metformin?
- First line choice with therapeutic lifestyle changes
- To minimize GI effects, take with food and start at a low dose to then titrate slowly up
- Contraindicated in pts with severe renal impairment (GFR<30), liver disease, alcohol abuse, unstable or acute HF, hemodynamic instability due to infection
- Temporarily discontinue metformin in patients at risk of developing lactic acidosis- IV iodinated contrast material (contrast nephropathy), acute dehydration or sepsis
What are examples of thiazolidinediones (TZDs)?
Pioglitazone and rosiglitazone
What is the MOA of TZDs (-glitazones)?
Act as a PPARgamma agonist (nuclear receptor) that leads to gene transcription
- Fat: increases good adipocytokines and decreases bad adipocytokines with inflammatory cytokines (increases AMPK and insulin sensitivity)
- Skeletal muscle: increases GLUT4 translocation which increases glucose uptake
- Liver: decreases hepatic glucose production
What are therapeutic effects of TZDs?
- Decreases A1C by 1-1.5%= medium efficacy
- No hypoglycemia
- Lowers TGs and increases HDL-C
What are side effects of TZDs?
- Hepatotoxicity
- Edema from sodium/water retention
- Weight gain
- Increases bone fractures
- Increases bladder cancer risk (pioglitazone)
What are important considerations of TZDs?
- Relatively slow effects (takes 1-2 weeks for onset and months for full effect)
- Baseline LFTs and check often
- Monitor signs for HF (increased risk if combined with insulin)
- Contraindications: HF, bladder cancer, fracture risk. active liver disease
What are examples of sulfonylureas?
Glimepiride, glipizide, and glyburide (second gens)
What are examples of non-sulfonylureas or meglitinides)
Nateglinide and repaglinide
What is the MOA for SUs and Non-SUs?
Bind to extracellular sulfonylurea receptor subunit of the ATP sensitive K channels on the B cell–> close K ATP channels–> depolarization–> increase activation of VGCC’s–> increase insulin secretion (still effective even if plasma glucose becomes too low)
T/F: SUs and Non-SUs are high efficacy drugs for lowering A1C
True
What are adverse effects seen with SUs and Non-SUs?
Hypoglycemia and weight gain
What are important considerations for SUs and Non-SUs?
- Risk factors for hypoglycemia: after exercise or missed meal, high dose, excessive alcohol, impaired renal/liver function
- Will not be effective in treating T1D since it works by using beta cells
What are examples of GLP-1 receptor agonists?
Exenatide, lixisenatide, liraglutide, dulaglutide, and semaglutide
What is the MOA for GLP-1 receptor agonists (-tide)?
Activates GLP-1 receptors that are coupled to Gs
- B cells- increased cAMP–> increased PKA–> VGCC–> insulin secretion (can also decrease B cell death)
- Delta cells- increased somatostatin leads to decreased glucagon from alpha cells
- GI- decreased gastric emptying leads to slow glucose absorption
- CNS- increased satiety
What are therapeutic effects seen in GLP-1 receptor agonists?
- High efficacy
- No hypoglycemia
- Weight loss (liraglutide)
- Lowers CV risk (liraglutide)
What are adverse effects seen with GLP-1 receptor agonists?
GI mainly- N/V/D
What are important considerations for GLP-1 receptor agonists?
- Administer SC
- Can be used off label for T1DM
- CI in patients with medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B cells
- Caution if there is a hx of pancreatitis
What are examples of DPP-4 inhibitors?
Sitagliptin, linagliptin, saxagliptin, alogliptin
What is the MOA of DPP-4 inhibitors (-gliptin)?
Inhibits DPP-4 on the surface of the capillary endothelium and decreases the breakdown of GLP-1 and other peptides–> increases endogenous effects of GLP-1
- B cell: increased cAMP–> increased PKA–> VGCC–> insulin secretion
What are therapeutic effects of DPP-4 inhibitors?
- low efficacy and only lowers A1C less than 1%
- No hypoglycemia
- Weight neutral
What side effects are seen in DPP-4 inhibitors?
- Increased risk of URI
- Rash
- Angioedema
- Joint pain (arthralgias)
But, in general these are well-tolerated
What is an important consideration for DPP-4 inhibitors?
Use with caution in patients that have a history or risk factors for heart failure, as this can increase the risk of hospitalization for HF
What are examples of SGLT2 inhibitors?
Canagliflozin, dapagliflozin, and empagliflozin
What is the MOA of SGLT2 inhibitors (-gliflozin)?
Inhibits SGLT2 in the proximal tubule and increases excretion of glucose (also inhibits this in alpha cells which increases glucagon)
What are therapeutic effects seen with SGLT2 inhibitors?
- Low efficacy and only lowers A1c<1%
- No hypoglycemia
- Weight loss (increased glucagon–> increased lipolysis)
- Lower blood pressure
- Lower CV risk
- Decreases progression of diabetic nephropathy
What are adverse effects seen with SGLT2 inhibitors?
- Genitourinary infections
- Hypotension
- AKI
- Euglycemic DKA
- Increase risk of lower limb amputations (canagliflozin)
What are important considerations for SGLT2 inhibitors?
- Used off label for T1D
- Educate about UTI prevention
- Drink lots of water to prevent hypotension and falls
- Risk factors for AKI (NSAIDS, ARBS, ACEIS)
- CI: severe renal impairment (GFR<45-60)
- Baseline kidney functioning and monitoring
- Risk factors for euglycemic DKA= less food intake, lower insulin dose, increase ETOH or infection
- Caution in patients with neuropathy, foot deformities, PAD
