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The six classes of medications in this category include:  sulfonylureas, meglitinides, thiazolidinediones, biguanides, alpha-glucosidase inhibitors, and agents that increase GLP-1.  These classes can be grouped together based on their mechanism of action. (NOTE: Drugs on the SHARING formulary are indicated in red; see formulary for specific details.)

• Drugs that stimulate the pancreas to produce more insulin: Sulfonylureas, meglitinides, and agents that increase available GLP-1. 
• Drugs that sensitize the body to insulin or control hepatic glucose production: Thiazolidinediones, biguanides, and agents that increase available GLP-1.
• Drugs that slow the absorption of starches:  Alpha-glucosidase inhibitors, and agents that increase available GLP-1.

Biguanides

• General: First line therapy, weight neutral.
• Mechanism of Action: Decreases hepatic gluconeogenesis and sensitizes skeletal muscle to insulin, which promotes glucose uptake.
• Dosing: Initial dose: 500 mg PO with breakfast and dinner. If GI side effects have not occurred after 5-7 days, increase dose to 1000 mg PO with breakfast and dinner. Maximum effective dose: 2000 mg per day. Three weeks for maximum clinical effect.
• Major Side Effects: Diarrhea and abdominal discomfort; can prevent lactate clearance so not recommended for those at increased risk of lactate production (e.g., renal insufficiency with serum creatinine >1.4 mg/dL in females and >1.5 mg/dL in males, liver disease, heart failure, hospitalized patient, on the day and two days after a planned contrast procedure, which can lead to higher risk of acute renal failure in diabetic patients)
• Contraindications: CrCl Creatinine clearance <30 ml/min due to increased risk of lactic acidosis.
• Common Medications: Metformin and metformin-ER (Glucophage®, Glucophage-XR®).

Sulfonylureas

• General: Given in addition to metformin to control BG.
• Mechanism of Action: Stimulates postprandial insulin secretion from pancreatic b-cells.
• Dosing: Glipizide initial dose: 5 mg PO once daily, 30 minutes before breakfast. The usual maintenance dosage is 10—15 mg PO once daily. Maximum recommended dosage is 40 mg/day for regular-release glipizide. Maximum clinical effect in 1 week. Note that glipizide is available as a generic extended release medication, which may improve compliance as it can be given once daily. Glimeperide can also be given once daily for full effect. All other medications must be split into BID dosing if giving more than half maximal dose.
• Major Side Effects: **Hypoglycemia**, may be greater with liver and kidney disease. Weight gain.
• Contraindications: DKA, caution with liver impairment or in elderly patients.
• Common Medications: Glipizide or glipizide-ER (Glucotrol® or Glucotrol XL®), glyburide (Micronase®, Glynase®, or DiaBeta®), & glimepiride (Amaryl ®).

Thiazolidinediones (a.k.a “glitazones” or “TZD’s”)

• General: Less well-validated therapy, added to metformin to control BG. No hypoglycemia and improves lipid profile.
• Mechanism of Action: Decrease insulin resistance by making target tissues (e.g., adipose cells) more sensitive to insulin. It also suppresses gluconeogenesis in the liver.
• Dosing: Initial dose: 15 mg or 30 mg PO once daily. Max dose is 45 mg PO once daily. Maximum clinical effect in 12 weeks.
• Major Side Effects: Weight gain, edema, exacerbation of heart failure (do not use with Class III or IV heart failure); liver function abnormalities are rare (<0.2%).
• Contraindications: Hepatic failure, heart failure.
• Common Medications: Pioglitazone (Actos ®) & rosiglitazone (Avandia ®) .

Alpha-Glucosidase Inhibitors

• Mechanism of Action: Competitively inhibits monosaccharide and oligosaccharide hydrolysis in the small intestine to decrease carbohydrate absorption.
• Major Side Effects: Abdominal discomfort & flatulence.
• Contraindications: May worsen symptoms of inflammatory bowel disease.
• Common Medications: Acarbose (Precose®) & miglitol (Glyset®).

Meglitinides

• Mechanism of Action: Stimulates insulin release from pancreatic b-cells very rapidly and for a short duration (has to be taken directly before meals) but flexible in case of changing or intermittent meal schedules.
• Major Side Effects: **Hypoglycemia**, but less than with sulfonylureas because of shorter duration.
• Common Medications: Repaglinide (Prandin®) & nateglinide (Starlix®); note that nateglinide is the least potent of all oral agents with respect to its impact on A1C.

Glucagon Like Peptide-1 (GLP-1) agonists and Dipeptidyl peptidase (DPP) inhibitors that increase endogenous GLP-1 levels by inhibiting its metabolism

• General: These are expensive medications. Byetta has the advantage of weight loss. The patient must be willing to take injections. Used as last line add on to metformin, sulfonylurea, and Actos to control BG.
• Mechanism of Action: Enhances glucose-stimulated insulin secretion from islets and possibly enhances islet longevity, inhibits hepatic gluconeogenesis, slow intestinal transit time reducing immediate postprandial hyperglycemia and enhancing postprandial satiety and weight loss (more likely to occur with Byetta).
• Major Side Effects: Hypoglycemia if combined with other agents that stimulate insulin release, such as sulfonylureas; thus, sulfonylureas should be reduced by 50% at time of onset; nausea with Byetta only.
• Contraindications: Known gastroparesis or decreased intestinal transit time.

GLP-1 mimetic (Exanatide-Byetta)
Initial Dose: 5 mcg SQ 1 hour before breakfast and supper. After 1 month increase dose to 10 mcg SQ 1 hour prior to breakfast and supper.
Major side effects: Nausea.

DPP-IV Inhibitor (Sitagliptin-Januvia)
Initial Dose: 100 mg once daily.
Major side effects: Increased risk of upper respiratory tract infection, pancreatitis.

Symlin (Pramlinitide)

• General: Injectable medication that has a benefit of weight loss.
• Mechanism of Action: Simulates the hormone amylin, thereby increasing GI transit time, decreases glucagon production and decreases appetite.
• Dosing: 60 mcg SQ immediately before meals and increase to 120 mcg if no nausea occurs in 3 days. Need to cut rapid/short acting or 70/30 insulin dose in half.
• Major Side Effects: Nausea.