Flashcards in 04 Thera VI T2DM Oral Therapies Diane Deck (103):
What is the pathophysiology of the pancreas in T2DM?
Impaired insulin secretion. Progressive loss of beta cell function
What is the pathophysiology of the liver in T2DM?
Impaired insulin sensitivity. Increased gluconeogenesis (glucose production)
What is the pathophysiology of the muscle and adipose tissue in T2DM?
Insulin resistance. Decreased glucose uptake
What is the pathophysiology of the GI tract in T2DM?
Site of glucose absorption. Decreased prandial response to glucose and incretin effect
What are the ADA adult glycemic goals?
A1c < 7%. FPG 70-130. 2hr PP < 180
What are the AACE adult glycemic goals?
A1c < 6.5%. FPG < 110. 2hr PP < 140
What drugs are Biguanides?
What is the MOA of Metformin?
Activates AMP-kinase: Decreases hepatic glucose production, decreases GI glucose absorption, improves peripheral glucose sensitivity
What is the A1c efficacy of Metformin?
Decreases it by 1-2%
What is the positive side of using Metformin?
NO weight gain or hypoglycemia associated. Can also improve the lipid panel (Decrease TG and LDL)
What is the Onset time of Metformin?
Days, max effect up to 2 weeks
How is Metformin metabolized/excreted?
No hepatic metabolism. 100% renally excreted
How is Metformin dosed?
Initial: 500mg BID or 850mg daily. Max: 2550mg/day (no added benefit > 2g/day)
How is Metformin ER dosed?
Initial: 500mg/day. Max 2000mg/day
What needs to be remembered about the administration of Metformin?
TAKE WITH FOOD. Titrate slowly
What are the common ADRs associated with Metformin?
GI effects: N/V/D, flatulence, abdominal discomfort (these are less with ER)
What are the counseling points with Metformin?
Recommend patients to take with food to decrease GI side effects. The side effects are transient, will improve over time
What is a rare side effect of Metformin (BBW)?
Lactic Acidosis. Risk increases with renal impairment and hypoxemia. Labs will show an increase in lactate (>5mmol), decreased blood pH, and electrolyte abnormalities (increase in anion gap)
What are the symptoms of Lactic Acidosis?
Very non-specific (need labs to prove it). N/V/D, hyperventilation, malaise, lethargy, myalgias
What are the contraindications associated with Metformin?
Hypersensitivity. Renal dysfunction (Scr > 1.5 for men and > 1.4 for women). Acute or chronic metabolic acidosis. Radiological studies with iodinated contrast (hold 48 hours prior to and after procedure)
What should you use caution with Metformin?
Chronic hepatic dysfunction (reduced lactate clearance). Hypoxic states (excessive alcohol, CHF, surgery)
What are the indications for Sulfonylureas?
Considered second-line to be added on to metformin and combination with insulin or other oral agents (except meglitinides). Can be used first-line in patients who cannot tolerate metformin
What are the main Sulfonylureas used?
Glimeperide (Amaryl). Glipizide (Glucotrol). Glyburide (DiaBeta, Micronase, Glynase)
What is the MOA of Sulfonylureas?
Binds ATP-dependent K channels --> depolarization of B-cells --> Ca influx --> increase insulin release. Partially reverses insulin secretory defect associated with T2DM
What is a drawback to Sulfonylurea use?
Effectiveness will decline over time
How much do Sulfonylureas decrease A1c?
1-2%. All agents equally effective
How are Sulfonylureas metabolized and eliminated?
Metabolism: Hepatic. Elimination: Renal (urine), feces
Which Sulfonylurea has the fastest onset?
Glyburide (1h). Glipizide (1-3h). Glimepiride (2-3h)
Which Sulfonylurea has the shortest duration of action?
Glipizide (10-14h). Glyburide (12-24). Glimepiride (24h)
Which Sulfonylureas have active metabolites?
Only Glimepiride and Glyburide
What are the CrCl levels that you need to use caution with the Sulfonylureas?
Glipizide (< 10). Glimepiride (< 22). Glyburide (< 50)
Which Sulfonylureas need to be taken with food?
"-ride": Glimepiride and Glyburide
When does Glipizide need to be taken?
Take 30 minutes before meals
Which Sulfonylureas have BID dosing?
Glyburide and Glipizide
Which Sulfonylureas have QD dosing?
Glimepiride and Glipizide ER
What are the common ADRs associated with Sulfonylureas?
Hypoglycemia. Weight gain (2-5kg)
What are the rare ADRs associated with Sulfonylureas?
GI (N, dypepsia). Photosensitivity. Skin rash
Which Sulfonylurea is usually ok to use with Sulfa allergies?
What are contraindications for Sulfonylurea use?
Hypersensitivity. T1DM (they don't have working B-cells to release insulin). Diabetic Ketoacidosis
When should you use caution when using a Sulfonylurea agent?
Sulfa allergy. Renal dysfunction
When are Meglitinides recommended?
May be used first line in patients who cannot take metformin or in place of SFU in patients with irregular eating schedules
What are the Meglitinide drugs?
Repaglinide (Prandin) and Nateglinide (Starlix)
What is the MOA of Meglitinides?
Similar to SFU (increase insulin production). Fast onset and shorter duration. Target post-prandial glucose
How much is A1c lowered by Meglitinides?
How are Meglitinides metabolized and eliminated?
Metabolism: Hepatic. Elimination: Renal (urine), feces
What is the onset time for Meglitinides?
Nateglinide (20 hours). Repaglinide (15-60 hours)
When are Meglitinides taken?
Taken with meals. Skip dose if skipping meal. Start with lowest possible dose (caution in elderly)
What are the common ADRs associated with Meglitinides?
Hypoglycemia (Repaglinide > Nateglinide). Weight gain. HA. Upper respiratory infection
When are Meglitinides contraindicated?
Hypersensitivity. T1DM. DKA. Repaglinide: concurrent gemfibrozil therapy
When should you use caution before Meglitinide use?
Caution in renal/hepatic impairment
When are Thiazolidinediones indicated?
Approved for monotherapy and combination therapy with metformin, DPP-4 inhibitors, incretin mimetics, SFU
What are the Thiazolidinediones drugs?
Prioglitazone (Actos). Rosiglitazone (Avandia)
What is the MOA of Thiazolidinediones?
Activate PPARy nuclear receptors (muscle and fat tissue). Decrease peripheral insulin resistance (insulin sensitizer). Decrease hepatic glucose output
How much is A1c lowered by Thiazolidinediones?
How do Thiazolidinediones affect the lipid profile?
Pioglitazone: decrease TG and increase HDL. Rosiglitazone: Increase LDL
What is the onset time for Thiazolidinediones?
Delayed. Up to 3 months for maximum effect. Works on gene translation, protein production
How are Thiazolidinediones metabolized and eliminated?
Metabolism: Hepatic. Elimination: Urine and feces
What is the BBW associated with Thiazolidinediones?
CHF (may cause or worsen CHF, not recommended for patients with symptomatic HF (class III and IV). Monitor patients for s/sx of HF after initiation and when increasing dose
What is cardiovascular safety like for Thiazolidinediones?
43% higher incidence of MI with Rosiglitazone use. Pioglitazone have some CV protection
What is the use of Rosiglitazone limited to?
Patients already being successfully treated with it. Patients who cannot be controlled with other anti-diabetic medicines. Consulted with MD and do not wish to use pioglitazone containing medicines
What is a major risk of Pioglitazone use?
Risk of bladder cancer increased with increasing dose (reaching statistical significance after 24 months). Do not use Pioglitazone for longer than 1 year. Counsel patients to report s/sx of blood in urine, urinary urgency, pain on urination, or back or abdominal pain
What is the administration of Thiazolidinediones like?
Once daily dosing. Can take without regard to meals. Brand only. No renal dose adjustment
What are the common ADRs associated with Thiazolidinediones?
Weight gain. Edema. Increased subcutaneous adipose
What are the rare ADRs associated with Thiazolidinediones?
Hepatic failure. Decreased WBC, Hgb, and platelets
What are the contraindications to Thiazolidinediones use?
NYHA Functional Class III/IV HF. ALT > 2.5x upper normal limit
When should you use caution before Thiazolidinediones use?
Cardiac disease. Edema. Hepatic disease. Bladder cancer (Pioglitazone)
When are alpha-Glucosidase Inhibitors indicated?
Approved for monotherapy or combination with metformin
What are the alpha-Glucosidase Inhibitors drugs?
Acarbose (Precose). Miglitol (Glyset)
What is the MOA of alpha-Glucosidase Inhibitors?
Decrease absorption of carbohydrates in small intestines. Inhibit small intestine brush border enzymes. Targets post-prandial glucose
How much is the A1c lowered with alpha-Glucosidase Inhibitors?
What is the absorption like for alpha-Glucosidase Inhibitors?
Acarbose is poor (1-2%). Miglitol has saturable absorption (25mg completely absorbed, 100mg ~50-70% absorption)
How are alpha-Glucosidase Inhibitors metabolized and eliminated?
Metabolism: Acarbose metabolized by intestinal bacteria and digestive enzymes in GI, Miglitol is not metabolized. Excretion: Renal (miglitol), fecal (acarbose)
What is the administration of alpha-Glucosidase Inhibitorslike?
Taken with meals. Skip dose if skipping meal. Slow titration - based on one hour post-prandial and to decrease GI upset
What are the common ADRs assocaited with alpha-Glucosidase Inhibitors?
GI side effects (gas, bloating, diarrhea)
What are the rare ADRs associated with alpha-Glucosidase Inhibitors?
Increased LFTs. Hepatic failure
What are the contraindications for alpha-Glucosidase Inhibitors?
Chronic GI disease (IBD, Crohns, obstruction)
When should you use caution before using alpha-Glucosidase Inhibitors?
What are the indications for Dipeptidyl Peptidase-4 (DPP-4) Inhibitors?
Approved for monotherapy and in combination with metformin, TZDs, SFUs
What are the DPP-4 Inhibitors drugs?
Sitagliptin (Januvia). Saxagliptin (Onglyza). Linagliptin (Tradjenta)
What is the MOA of DPP-4 Inhibitors?
Inhibit DPP-4 --> increase endogenous incretins (GLP-1 and GIP). Early satiety. Increase insulin release in response to ingested glucose. Decrease pancreatic secretion of glucagon. Slowed gastric emptying
How much is A1c lowered with DPP-4 Inhibitors?
Which DPP-4 Inhibitors are excreted renally?
Which DPP-4 Inhibitor is excreted 80% bile (enterohepatic), minimal renal?
How is Sitagliptin renally adjusted?
CrCl 30-50: 50mg daily. CrCl < 30: 25mg daily
How is Saxagliptin renally adjusted?
CrCl < 50: 2.5mg daily
How is Linagliptin renally adjusted?
No renal adjustment needed
What are the ADRs associated with Sitagliptin?
GI side effects. URI. Nasopharyngitis
What are the ADRs associated with Saxagliptin?
Peripheral edema. Hypoglycemia
What are the ADRs associated with Linagliptin?
What is the combination product: Metformin + Glyburide?
What is the combination product: Metformin + Glipizide?
What is the combination product: Metformin + Pioglitazone?
What is the combination product: Metformin + Rosiglitazone?
What is the combination product: Metformin + Sitagliptin?
What is the combination product: Metformin + Linagliptin?
What is the combination product: Glimeperide + Pioglitazone?
What is the combination product: Glimperide + Rosiglitazone?
What are your best drug choices to avoid weight gain?
Metformin. DPP-4 Inhibitors
What are the best drug choices to avoid GI symptoms?
SFUs. Meglitinides. TZDs. DPP-4 Inhibitors
What are the best drug choices to avoid Hypoglycemia?
Metformin. TZDs. DPP-4 Inhibitors
What are the best drug choices with impaired renal function?
What are the best drug choices with impaired hepatic function?
SFUs. DPP-4 Inhibitors