Oral Diabetes Meds Flashcards
Biguanides
Example: Metformin
MOA: Activates AMPK in hepatocytes and skeletal muscle –> complex metabolic effects include decrease ATP consuming reactions and increase ATP producing reactions; increase insulin sensitivity
- Hepatocytes: decrease gluconeogenesis –> decrease hepatic glucose production decrease cholesterol, TG, and FA synthesis
- SKM: increase GLUT4 translocation –> increase glucose uptake
Therapeutic effects:
1. decrease A1c > 1.5% (high efficacy)
2. No hypoglycemia
3. decrease plasma glucose –> decrease plasma insulin (decrease ovarian androgen production –> adjunctive therapy for PCOS to restore ovulation)
4. decrease LDL-C, decrease TGs, increase HDL-C
5. Weight neutral/Weight loss?
AEs:
1. GI - very common
Diarrhea, nausea, abdominal discomfort,
metallic taste, decrease vitamin B 12 absorption
(Possibly involves increased intestinal lactate production?)
2. Lactic acidosis - very rare!
More likely if patient has underlying risk factors
- decrease kidney function
- Tissue hypoxia (e.g., cardiopulmonary disease)
- Liver disease and excessive alcohol use
Important Considerations
1. First line choice with therapeutic lifestyle changes
2. To minimize GI AEs, take with food, start with low dose, and titrate slowly
3. Contraindicated in patients with predisposing factors to lactic acidosis:
- severe renal impairment (eGFR < 30 ml/min)
- concurrent or active liver disease or active ETOH abuse
- unstable or acute HF
- hemodynamic instability due to infection or other causes
4. Temporarily discontinue metformin in patients at risk of developing lactic acidosis:
- IV iodinated contrast material (contrast nephropathy)
- acute dehydration or sepsis
Thiazolidinediones (TZDs)
Examples: Pioglitazone, Rosiglitazone (Glitazones)
MOA: PPARγ agonist (nuclear receptor) –> gene transcription
- Fat: increase good adipocytokines, decrease bad adiposecytokines (increase AMPK and insulin senstitvity at target tissues)
—-decrease inflammatory cytokines
- SKM: increase GLUT4 translocation –> increase glucose uptake
- Liver: decrease Hepatic glucose production
Therapeutic effects:
1. decrease A1c 1-1.5% (medium efficacy)
2. No hypoglycemia
3. decrease TGs, increase HDL-C (pioglitazone)
AEs:
1. Hepatotoxicity
2. Sodium/water retention –> edema
3. Weight gain (fluid retention, new adipocytes? CNS effect?)
4. increase Bone fractures (decrease osteoblast function?)
5. increase Bladder cancer risk (pioglitazone)
Important Considerations:
1. Relatively slow effects (1-2 weeks onset; 2-3 months
max effect: due to genomic effects?)
2. Baseline LFTs/Check LFTs
3. Monitor for signs of HF ( rapid wt gain, dyspnea, edema) *increase risk if combined with insulin
4. Contraindications:
- HF
- Active bladder cancer or history of bladder - cancer
- History of fracture or high risk of bone fracture
- Active liver disease
Sulfonylureas and Non-Sulfonylureas
Examples:
S: Glimepiride, Glipizide, Glyburide (2nd gen)
N-S: Nateglinide, Repaglinide (Meglitinides)
MOA: Bind to the extracellular “sulfonylurea receptor subunit” of the ATP sensitive K+ (KATP) channels on the β cell –> close KATP channels –> depolarization –> increase activation of voltage-gated Ca2+ channels –> increase insulin secretion
(Still increases insulin secretion even if plasma glucose becomes too low!)
Therapeutic effects:
1. decrease A1c > 1.5% (high efficacy)
AEs: Hypoglycemia (“oral hypoglycemics”)
- palpitations, tremors, sweating, anxiety (increase SNS), hunger (increase PNS), CNS symptoms (increase neuroglycopenia)
Weight gain (increase insulin effect)
Important Considerations:
1. Risk factors for hypoglycemia
- After exercise or a missed meal
- Drug dose is too high
- Excessive ETOH use
- Impaired renal or liver function (depending on how drug is metabolized)
2. Will not work in T1DM patients (no β cells)
GLP-1 Receptor Agonists (Incretin Mimetics)
Ex: Exenatide, Lixisenatide, Liraglutide, Dulaglutide, Semaglutide
MOA: Activates GLP-1 receptors ( coupled to Gs)
- β cell: increase cAMP –> increase PKA –> increase opening of voltage-gated Ca2+ channels in response to depolarization –> increase “glucose-mediated” insulin secretion
(Also may decrease β cell death)
- δ cell: increase somatostatin–> decrease glucagon from α cells
- GI: decrease gastric emptying –> slow glucose absorption
- CNS: increase satiety
Therapeutic effects:
1. decrease A1c > 1.5% (high efficacy)
2. No hypoglycemia
3. Weight loss (Liraglutide approved)
4. decrease CV risk (Liraglutide approved)
AEs:
1. GI:
-Nausea/vomiting (GI mediated? )
-Diarrhea
Important Considerations:
1. Administer SC
2. Off-label use in T1DM
3. Contraindicated in patients with medullary
thyroid cancer or multiple endocrine
neoplasia (MEN) 2A or 2B (stimulation of GLP-1
receptors on thyroid C cells?)
4. Caution if there is a history of pancreatitis
DPP-4 Inhibitors (Incretin Mimetics)
Ex: Sitagliptin, Linagliptin, Saxagliptin, Alogliptin
MOA: Inhibits DPP-4 on the surface of capillary
endothelium –> decrease breakdown of GLP-1 and other peptides –> decrease endogenous effects of GLP-1, but not exactly the same as GLP-1 agonists
- β cell
increase cAMP –> increase PKA –> increase opening of voltage-gated
Ca2+ channels in response to depolarization
–> increase ”glucose-mediated” insulin secretion
Therapeutic effects:
1. decrease A1c < 1% (low efficacy)
2. No hypoglycemia
3. Weight neutral
AEs: generally well tolerated
1. increase risk of upper respiratory infection (DPP-4 found on T lymphocytes?)
2. Rash
3. Angioedema (DPP-4 involved in bradykinin metabolism; increase risk if combined with ACEIs)
4. Joint pain (arthralgias)
Important Considerations
1. Use with caution in patients with history of or
risk factors for HF –> increase hospitalization for HF
SGLT2 Inhibitors
Ex: Canagliflozin, Dapagliflozin, Empagliflozin
MOA: Inhibits SGLT2 in proximal tubule –> increase UV(glucose)
-also inhibits SGLT2 on pancreatic alpha cells –> increase glucagon
Therapeutic effects:
1. decrease A1c < 1% (low efficacy)
2. No hypoglycemia
3. Weight loss – from increase glucagon –> increase lipolysis
4. decrease BP
5. decrease CV risk (maybe from decrease blood pressure, increase cardiac
ketone utilization –> decrease MVO2, decrease RAAS via macula densa mechanism )
6. decrease Progression of diabetic nephropathy
*Empaglifozin is approved for reduction in CV mortality in T2DM patients with established CV disease
AEs:
1. Genitourinary infections
2. Hypotension (osmotic diuresis –> volume depletion)
3. AKI (TGF mediated afferent arteriole vasoconstriction –> decrease PGC)
4. “Euglycemic” DKA
-ketoacidosis with Pglucose < 250 mg/dL
-increase glucagon –> increase lipolysis –> increase FA release –> increase ketogenesis
5. increase risk of lower limb amputations (canagliflozin)
Important Considerations:
1. Off-label use in T1DM
2. Patient education about prevention of genitourinary infection
3. Drink plenty of fluid to prevent orthostatic hypotension and falls
4. Risk factors for AKI ( Caution with NSAIDs, ARBs, ACEIs)
5. CI: severe renal impairment (eGFR < 45-60 ml/min)
6. Baseline renal function/monitoring
7. Risk factors for “euglycemic” DKA
-decrease food intake
-decrease insulin dose if taking with insulin
-increase ETOH intake
infection
(If patient develops nausea, abdominal pain, trouble breathing, should call
physician immediately and use ketone dipstick)
8. Caution in patients with neuropathy, foot deformities, PAD
