Oral Hypogycemic Drugs

Overview

Mechanisms

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.  
      • IN RENAL FAILURE USE INSULIN!
         
• 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.