Oral Hypogycemic Drugs





    Class Brand Names A1c Decr Dose Benefits Side/Effects Contraind.
    Metformin Glucophage 1995 1.0-1.5%

    Initial: 250mg BID (or 500 OD), titrate to 1000mg BID in 1-2 week intervals.

    Inhibits gluconeogenesis in liver + incr muscle/liver insulin sensitivity

    - Weight Loss/Neutral

    - Almost no hypoglycemia risk.

    - Improves lipid profile

    - Decr cardiac inflam. markers (CRP)


    - GI 10-15% (abdo discomfort, anorexia, bloating, diarrhea)

    - lactic acidosis (rare!)

    C/I: Mod-Severe liver or cardic dysfunction.



    Caution: <60 ml/min

    Contraindicated:  <30ml/min


    Glipizide (Glucotrol 1984)


    Glyburide (DiaBeta, Glynase, Micronase 1984)


    Glimepiride (Amaryl 1995)


    Glicazide (Diamicron)


    Glyburide: init 2.5mg AM; Max: 10mg BID

    Glimeperide: init: 1-2mg AM; Max: 8mg OD

    Gliclazide: Init: 80-160mg OD; Max 160mg BID

    MR form: 30-120mg OD

    Gliclazide MR: Init 30mg OD (1tab); Max 120mg OD (4tabs)

    Sensitize B-islets to glucose, increase insulin secretion.

    Rapid glucose response

    - Hypoglycemia (esp w/ glyburide)

    - Weight Gain

    C/I: Mod-Severe liver dysfunction + adjust dose in renal dysfunction:


    Stop if CrCl/eGFR: 


    Exception: Diamicron <30ml/min


    Repaglinide (Prandin 1997)


    Nateglinide (Starlix 2000)


    Repaglinide: 1.0-2.0%

    Nateglinide: 60-120mg TID w/ meal (Cyp2C9)

    Repaglinide: 0.5-4mg TID w/ meal (Cyp3A4)

    - Useful for treating postprandial hyperglycemia

    - Use with each meal. Do not use with sulfonylureas (other OHA are ok)


    Weight Gain


    Safe, BUT titrate dose slowly!

    - No long-term data yet.



    (Avandia 1999)


    Pioglitazone (Actos 1999)


    Pioglitazone: 15 or 30 or 45mg OD

    Rosiglitazone: 2 or 4 or 8mg OD (off market - CVS events)

    Work through PPAR proteins, insulin sensitizers (muscle + adipose)


    - Long duration of glycemic control

    - Weight neutral

    - Weight Gain - Edema (bad in CHF)

    - anemia

    - Pulmonary edema


    - Increased CV events in rosiglitazone

    C/I: severe liver dysfunction or NYHA class II-IV CHF


    No CrCl adjustment necessary




    (Glucobay 1995)



    (Glyset 1996)

    <1.0% 25-100mg TID w/ meal

    Inhibit sucrose breakdown.

    S/E: flatulence, bacterial overgrowth, osmotic diarrhea.

    Effective in prediabetes

    Weight Neutral

    GI side effects

    Limited A1c lowering effects


    - IBS

    - Severe kidney/liver dysfunction.

    DPP-4 inhibitor

    Sitagliptin (Januvia 2006)


    Saxagliptin (Onglyza 2009)


    Sitagliptin: 100mg PO OD

    Saxagliptin 2.5-5mg PO OD

    Weight Neutral

    Low risk of hypoglycemia


    Pancreatitis (rare)

    SJS (rare)


      30-60ml/min 50mg OD

       <30ml/min 25mg OD


      <50ml/min 2.5mg OD






    0.6mg SC OD for 2wk; then increase to 1.2mg sc OD x2wk; then 1.8mg OD




    Little Hypoglycemia

    GI symptoms

    C-Cell Hyperplasia

    (ask FMHx MEN)

    Pancreatitis (rare)

    No adjustment

    Little experience in renal failure

    Lipase Inhibitor


    (for obese pts only)

    0.3-0.9% 120mg TID

    Decreased intestinal fat absorption 

    - Weight loss!



    - Less fat soluble vitamin absorption.

    - GI fatty stools


    - Malabsorption syndrome

    - Cholestasis













    100mg PO daily then 

    300mg po daily

    EMPA-REG study

    (Empagliflozin) CV





    • HypoglycemicsMechanisms.jpg


    Drug by Drug

    • a-Glucosidase inhibitors

      • Only Acarbose available in Canada
        • Start Acarbose at 25mg once daily, titrate up to 100mg TID
      • Competitive inhibition of enzymes in small intestine that break down oligosaccharides and disaccharides into monosacharides.  Absorption is delayed, and shifted to distal parts of bowel.  Most excreted in feces.
      • Efficacy:
        • Blood glucose lowering effect is less than other OHAs.
        • Average HbA1c lowering 0.5-1.0% + small reduction in TG levels.
        • No effect on fasting glucose (only post-prandial).
      • Side Effects
        • GI:
          • Over growth of GI bacteria
          • Bloating, abdo discomfort, diarrhea, flatulence (20%).
        • Contraindicated: in IBS, IBD (relative), renal or liver dysfunction.
    • Biguanides

      • Examples: Metformin, phanformin, buformin
        • All but metformin removed from international market in 1970's - risk of lactic acidosis (poor evidence).
      • Mechanism:
        • Unclear.  Likely decrease in hepatic glucose output (inhibits glyconeogenesis).
        • Also increase in muscle glucose uptake. 
        • Some evidence activates hepatic & muscle AMP kinase --> alters perceived energy requirements.
      • Efficacy:
        • Lowered HbA1c 1.0-1.5% (placebo-controlled)
        • Equivalent to sulfonylurea monotherapy.
        • Weight loss, or at least no weight gain.  Improvement in lipid profile.
          • Decreased plasminogen activator inhibitor-1 and CRP (ass'd with decrease cardiac risk)
        • 36% relative risk reduction of all-cause mortality, 
        • Can be used in Type I diabetes to reduce insulin requirements. (not approved indication)
      • Side Effects
        • GI (10-15%): abdo discomfort, anorexia, bloating, diarrhea.
          • Start LOW (even 250 mg/day) titrate slowly up every 1-2 weeks to 1000mg BID
          • 4% discontinue due to GI S/E.
        • No risk of hypoglycemia!  Does not alter insulin secretion.
        • Lactic acidosis: Extremely rare.  Initially seen with Phenformin, which is taken off the market.
          • Monitored metformin safety over 56000 patient years: extremely low risk of lactic acidosis.  8.4 cases/100,000 patient-years for metformin group vs. 9 cases/100,000 pt-years in placebo.
          • Phemformin elimination required liver conjugation.  Metformin excreted unchanged via kidneys, so this problem is not as pronounced.
      • Contraindications/Warnings:
        • Renal dysfunction - metformin can accumulate.
          • Reduce dose in mild renal failure (keep in mind creatinine can fluctuate).
          • Mod-Severe renal failure use extreme caution or do not use.  
    • Insulin Secretagogues:
      • Sulfonylureas
      • Non-Sulfonylureas
    • Sulfonylureas

      • Insulin secretagogue.
      • Currently available in Canada:
        • Gliclazide (short acting (BID) and long acting MR (OD) forms)
        • Glimepiride (OD dosing)
        • Glyburide  (higher risk of hypoglycemia esp in renal failure, but cheapest!)
        • Others: chlorpropamide and tolbutamide. (RARE)
      • Dosing:
        • Start with low dose, titrate up q1-2 weeks to desired glycemic control.  
        • Gliclazide available in short  acting (BID) and MR long acting (OD) forms.
      • Mechanism:
        • Bind receptor on surface of pancreatic B-cells.  Close potassium channels --> prevents hyperpolarization of the B-cell --> decreases active potential threshold --> Influx of calcium causes microtubules to contract --> exocytosis of insulin vesicles. 
        • DO NOT affect insulin sensitivity directly.  This is an indrect effect due to better glucose control.
      • Efficacy:
        • 1.0-1.5% effective
        • Study: sulfonylureas vs. insulin --> reduction in microvascular compl in sulfonylurea group.
      • Side Effects:
        • HYPOGLYCEMIA!! Tirate slowly!  Incidence 1-2%/year.
          • Often resolve with PO sugar or fruit juice.  Can be prolongued if renal/liver failure.
        • Weight gain. 
      • Contraindications/Warnings:
        • Metabolized by liver, cleared by kidneys.
          • Glyburide breakdown metabolites are active.  In renal failure accumulate to cause hypoglycemia.
          • Gliclazide and glimepiride are metabolized by liver to inactive metabolites.
        • DO NOT use in moderate to severe liver dysfunction.
          • Significant renal dysfunction --> not enough data.  Just use insulin.
        • Concern of cross-reactivity to sulfa allergy
          • Studied: Likely no cross-reactivity.  Rather the effect is due to genetic predisposition to be allergic to both.  (only retrospective studies).  Controversial. 
    • Non-Sulfonylurea Secretagogues:

      • Relatively new class (as of 2005)
        • Nateglinide and Repaglinide
      • Mechanism:
        • Similar to sulfonylureas.  Closing K+ channel --> calcium dependent insulin secretion.
        • But bind to different site --> onset faster, half-life shorter.
          • = Brief stimulation of insulin release
        • Metabolized by liver CypP450 --> biliary products.
          • Repaglinide - Cyp3A4
          • Nateglinide Cyp2C9.
    • Thiazolidinediones

      • In Canada:
        • Rosiglitazone
        • Pioglitazone.
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