Background Information on Oral Antihyperglycemic Agents (OAHAs)

  

BIGUANIDES (Metformin)

•    acts on liver to decrease hepatic production of glucose

•   because of clear evidence of its use to prevent complications in type 2 diabetes, should be FIRST-LINE treatment unless contraindicated

•    Advantages:

     - lowers A1C by 1.0-1.5%

     - no associated hypoglycemia (unless it is being taken while NPO or in a catabolic state)

     - weight neutral

     - affordable (on provincial formulary, ~ $12/month)

•    Disadvantages

     - common side effects: gastrointestinal (diarrhea, bloating): these typically subside in 1-2 weeks

     - can take up to 1-2 weeks to start to work

•    Tips for dosing:

     - start 500 mg BID and titrate up to 1000 mg BID

     - if GFR is btw 30-60 mL/min, consider limiting dose to 1000 mg/day

     - avoid if GFR <30 mL/min due to risk of lactic acidosis

•  Contraindications:

      - avoid in pts with GFR <30 mL/min and/or decompensated liver disease (risk of lactic acidosis)

     - hold if pt is about to receive IV contrast or is about to undergo surgery.  Restart safely after 48 hrs if renal function remains stable

 

INSULIN SECRETAGOGUES

•   two subclasses:

     -  sulfonylureas (glimepiride (Amaryl ฎ), gliclazide (Diamicron ฎ), gliclazide extended-release (Diamicron MR ฎ), glyburide (Diabeta ฎ))

    - meglitinides (nateglinide (Starlix ฎ), repaglinide (Gluconorm ฎ))

•  work quicker, shorter duration, safer in renal insufficiency

•    generally lower A1C by 1.0-1.5%

 •  Advantages:

    - quick acting

    - long-term data available (for sulfonylureas but not nateglinides)

    - sulfonylureas affordable (glyburide $9/month, gliclazide $23/month) and generally on formulary

    - can use gliclazide and meglitinides in renal failure (with caution)

    - meglitinides better prevent elevations in postprandial glucose.  They increase insulin secretion in a glucose-dependent manner (i.e. will not increase insulin if glucose is not high) and thus have less potential for hypoglycemia

 •   Disadvantages               

   - weight gain

   - risk of hypoglycemia (sulfonylureas > meglitinides; highest risk with glyburide, least with gliclazide)

   - meglitinides costly and NOT on formulary

 

Tips for dosing:

•  glyburide has much HIGHER risk of HYPOGLYCEMIA.  Gliclazide is a safer option and is on the formulary
•  start at higher doses if higher blood glucose (e.g. glyburide 2.5 mg BID will be ineffective if BS is >15).  Can decrease doses later as BS

  normalizes.

•  glyburide 10 mg BID is unlikely to be more effective than 5 mg BID

 

INCRETIN-BASED THERAPIES

 

General

•  physiology: incretins (e.g. GLP-1) enhance insulin secretion in response to a meal.  In type 2 diabetes, this is impaired

•  two classes of medications can enhance incretin action:

  - DPP-IV inhibitors: inhibits the enzymes that break down incretins

     - GLP-1 agonists

•  approved for use in combination with metformin or sulfonylureas

 

DPP-IV inhibitors (saxagliptin (Onglyza ฎ), sitagliptin (Januvia ฎ), linagliptin (Trajenta )

•  administered orally

• Advantages

   - taken orally once daily

   - weight neutral

   - simple titration and dosing

   - low risk for hypoglycemia

   - linagliptin safe in renal impairment (saxagliptin has renal dose of 2.5 mg, and sitagliptin has renal dose of 50 mg for CrCl 30-50 mL/min, and for CrCl <30 mL/min)

•  Disadvantages:

  - slightly less A1C-lowering compared to other classes (0.5 - 0.8% reduction)

   - costly (~$100/month), although they are all on ODB formulary

   - no long-term data

   - potential for drug interactions with saxagliptin but not sitagliptin

 

GLP-1 agonists (exenatide (Byetta ฎ), liraglutide (Victoza ))

• administered via a once-daily subcutaneous injection

• Advantages

    - similar A1C reduction to other classes

    - can result in weight loss (average 2-3 kg)

    - potential to regenerate beta cell activity (animal models)

    - low risk for hypoglycemia

    - decreases satiety

•  Disadvantages

    - costly ($170-250/month) and NOT on formulary

    - may get irritation at injection sites

    - avoid in renal failure

    - avoid in pancreatitis

    - no long-term data

 

Tips for dosing:

•  DPP-IV inhibitors:

     - Sitagliptin 100 mg OD

     - Saxagliptin 5 mg OD

     - Linagliptin 5 mg OD

•  GLP-1 agonists:

     - Liraglutide: start 0.6 mg SC OD, then increase to 1.2 mg SC OD (if no adverse effects like nausea).  Can increase further to 1.8 mg SC OD if needed.

     - Exenatide: given BID; may have more potential for GI adverse effects

 

THIAZOLIDENEDIONES (pioglitazone (Actosฎ), rosiglitazone (Avandiaฎ))

•    PPAR-gamma agonists, insulin sensitizers

•    Advantages:

     - lowers A1C by 1.0-1.5%, similar to other classes

     - low risk for hypoglycemia when used on its own

•   Disadvantages:

    - weight gain

    - risk of fluid retention and worsened CHF

    - “media effect”: public concerns re: heart, bone, bladder CA (pioglitazone)

 

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