Table of contents
- 1. Overview
- 2. Mechanisms
- 3. Drug by Drug
- 3.1. a-Glucosidase inhibitors
- 3.2. Biguanides
- 3.3. Sulfonylureas
- 3.4. Non-Sulfonylurea Secretagogues:
- 3.5. Thiazolidinediones
.
Overview
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.
CrCl/eGFR: Caution: <60 ml/min Contraindicated: <30ml/min |
Sulfonylurea | Glipizide (Glucotrol 1984)
Glyburide (DiaBeta, Glynase, Micronase 1984)
Glimepiride (Amaryl 1995)
Glicazide (Diamicron) | 1.0-1.5% | 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: <50ml/min Exception: Diamicron <30ml/min |
Meglitanides | Repaglinide (Prandin 1997)
Nateglinide (Starlix 2000) | Nateglinide:<1.0% 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) | Hypoglycemia Weight Gain
| Safe, BUT titrate dose slowly! - No long-term data yet. |
TZDs | Rosiglitazone (Avandia 1999)
Pioglitazone (Actos 1999) | 1.0-1.5% | 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 Osteoporosis - Increased CV events in rosiglitazone | C/I: severe liver dysfunction or NYHA class II-IV CHF
No CrCl adjustment necessary |
Alpha-Glucosidase Inhibitor | acarbose (Glucobay 1995)
Miglitol (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 | Contraind.: - IBS - Severe kidney/liver dysfunction. |
DPP-4 inhibitor | Sitagliptin (Januvia 2006)
Saxagliptin (Onglyza 2009) | 1.0-2.0% | Sitagliptin: 100mg PO OD Saxagliptin 2.5-5mg PO OD | Weight Neutral Low risk of hypoglycemia | GI Pancreatitis (rare) SJS (rare) | Sitagliptin: 30-60ml/min 50mg OD <30ml/min 25mg OD Saxagliptin: <50ml/min 2.5mg OD |
GLP-1 Agonists | Liraglutide (Victoza) | 1.0-2.0% | 0.6mg SC OD for 2wk; then increase to 1.2mg sc OD x2wk; then 1.8mg OD Onwards
| LOOSE WEIGHT Little Hypoglycemia | GI symptoms C-Cell Hyperplasia (ask FMHx MEN) Pancreatitis (rare) | No adjustment Little experience in renal failure |
Lipase Inhibitor | Orlistat (for obese pts only) | 0.3-0.9% | 120mg TID | Decreased intestinal fat absorption - Weight loss!
| - Less fat soluble vitamin absorption. - GI fatty stools | C/I: - Malabsorption syndrome - Cholestasis |
SGLT-2 Inhibitors | Canagliflozin (Invokana)
Empagliflozin (Jiardiance)
Dapagliflozin (Farxiga) | Canagliflozin 100mg PO daily then 300mg po daily | EMPA-REG study (Empagliflozin) CV outcomes |
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.
- GI:
- Only Acarbose available in Canada
-
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.
- GI (10-15%): abdo discomfort, anorexia, bloating, diarrhea.
- 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!
- Renal dysfunction - metformin can accumulate.
- Examples: Metformin, phanformin, buformin
- 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.
- HYPOGLYCEMIA!! Tirate slowly! Incidence 1-2%/year.
- 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.
- Metabolized by liver, cleared by kidneys.
-
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.
- Relatively new class (as of 2005)
-
Thiazolidinediones
- In Canada:
- Rosiglitazone
- Pioglitazone.
- In Canada:
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