Introduction
Oral Agents
     General Considerations
     Oral Hypoglycemic Agents (OHAs)
     Oral Hyperglycemic Agents (AHAs)
     Sulfonylureas
     Biguanides
     Alpha-Glucosidase Inhibitors
     Thiazolidinediones
     Meglitinides
     Customizing Pharmacotherapy for Type 2 Diabetes: Summary Considerations
References

Introduction

• The Diabetes Epidemic
• 15.7 million Americans have diabetes
• Approximately 6% of the population
• One-third are undiagnosed, therefor, untreated
• Approximately 100 million people have diabetes worldwide
• 5-10% have type 1 diabetes
• 90-95% have type 2 diabetes
• Diabetes on the rise
• Not due to changes in the disease or its treatment
• Associated with older age, lack of physical exercise, and obesity
• Our population is older, less active, and more overweight
• Diabetes on the rise
  • Not due to changes in the disease or its treatment
  • Associated with older age, lack of physical exercise, and obesity
  • Our population is older, less active, and more overweight

Oral Agents

General Considerations

• 10-20% Primary failure with all oral agents
• Dosing (qd, bid, tid, etc.)
• Effects/Actions (Increase insulin production, decrease insulin resistance, etc.)
• Metabolism (liver, kidneys, etc.)
• Side Effects
• Cost

Oral Hypoglycemic Agents (OHAs)

• Reduce plasma glucose (by insulin production)
• Are insulin secretagogues
• May cause hypoglycemia
• Examples
  • Sulfonylureas
  • Meglitinides

Oral Hyperglycemic Agents (AHAs)

• Reduce blood glucose without ­ insulin levels
• Are non-insulin secretagogues
• Alone, will not cause hypoglycemia
• Examples
  • Biguanides
  • Alpha-Glucosidase Inhibitors
  • Thiazolidinediones

Sulfonylureas

• AKA: Oral Hypoglycemic Agents (OHA) –
• Effects
  • primarily stimulate insulin release from beta cells of pancreas
  • improves insulin utilization (mild effect)
• Require endogenous insulin
• Increased insulin production may cause:
  • Hypoglycemia
  • Weight gain
  • More hyperinsulinemia
• First and second generation agents
• Specific Agents
  • Tolazamide (Tolinase)
    • First generation
    • Similar side effect profile to 2nd generation agents
    • Low cost
  • Glipizide GITS (Glucotrol XL)
    • Second generation
    • Extended release - lower insulin levels than rapid release
  • Glimepride (Amaryl)
    • Second generation
    • Binds to different receptor than other sulfonylureas so may work if others don't
    • Only sulfonylurea approved by FDA for use with insulin
    • Reported lower incidence of hypoglycemic episodes

Biguanides

• Metformin (Glucophage)
• Antihyperglycemic agent
• Effects
  • Decrease glucose production in liver (primary effect)
  • Increase utilization in the cells (minor effect)
  • No stimulation of insulin release reduces insulin levels
• Indications
  • Monotherapy
  • Combination with Sulfonylureas
  • Combination with Pioglitazone
  • Combinations with Insulin
• Dosing
  • Incremental to minimize GI effects
  • Administer with meals
  • Start with 500 mg/day with largest meal and increase 500 mg/wk
  • Maximum dose 2550 mg/day given 850 mg TID

Metformin Incremental Dosing
	Week 1	Week 2	Week 3	Week 4
Breakfast	None	500 mg	500 mg	1000 mg
Lunch	None	None	None	None
Dinner	500 mg	500 mg	1000 mg	1000 mg

• In monotherapy equal to sulfonylureas
• Has synergistic effect when combined with sulfonylureas
• Precautions
  • Most adverse effects are GI – self limiting
  • Lactic Acidosis
  • May decrease B-12 absorption – check CBC every year
  • Caution with digoxin, procainamide, cimetidine, ranitidine, quinidine, vancomycin, triamterene, and other cationic drugs may increase metformin levels
• Contraindicated if:
  • Renal dysfunction (Creatinine > 1.4 in males, 1.3 in females or other sign of renal dysfunction)
  • Impaired hepatic function (no objective guidelines given)
  • Excessive alcohol consumption
  • Patients > age 80 unless Creatinine clearance tested and is normal
  • Patients being treated for CHF
  • Patients otherwise prone to lactic acidosis
• Discontinue metformin if
  • Pregnant
  • Undergoing surgical procedures
  • Undergoing x-rays with injected dye
  • Hypoxic state develops (acute MI or CHF, etc.)
  • Alcohol binging
  • Dehydration
• Unique characteristics
  • Improves lipids
  • May increase weight loss
  • Reduces hyperinsulinemia

Alpha-Glucosidase Inhibitors

• Acarbose (Precose), Miglitol (Glyset)
• Antihyperglycemic agents
• Effects
  • Delays absorption in intestine of complex carbohydrates
  • Doesn't stimulate insulin production
  • Reduces postprandial hyperglycemia and hyperinsulinemia
• Indications
  • Monotherapy
  • Combination with Sulfonylureas
  • Combination with Metformin
• Systemic absorption
  • Acarbose: slight (~3%) systemic absorption
  • Miglitol: 50-100% systemic absorption (higher at lower doses)
    • Effects are due to local effects, no known systemic effects
    • Eliminated by kidneys - no dose change with decreased kidney function
• Dosing
  • Initially 25 mg tid x 4 weeks or 25 mg once daily then increase weekly until tid

    Dosing Acarbose or Miglitol
    	At Start of Breakfast	At Start of Dinner/Supper
    Week 1		25 mg
    Week 2		25 mg
    Week 3	25 mg	25 mg
    Week 4	25 mg	25 mg

  • Maintenance 50-100 mg tid
  • Always take with first bite of each meal
  • Start low, titrate slow to reduce side effects
  • May reduce metformin levels
  • 50 mg of Miglitol = 100 mg of Acarbose
• Side effects: GAS and abdominal cramps and other GI
• Contraindications
  • Known hypersensitivity to Acarbose
  • DKA
  • Cirrhosis
  • Inflammatory bowel disease or patients predisposed to obstruction
  • Chronic digestion or absorption disorders
  • Conditions that may deteriorate with gas formation
• Precautions
  • Don't exceed 50 mg tid if weight < 60 pounds (Acarbose)
  • > 50 mg tid may cause reversible LFT changes (Acarbose)
  • If hypoglycemia occurs, must give glucrose or fructose. Sucrose is not absorbed.

Thiazolidinediones

• Rosiglitazone (Avandia), Pioglitazone (Actos), (Rezulin removed from market)
• Antihyperglycemic agent
• Effects
  • Insulin sensitizer – improves insulin sensitivity at the cellular level
    • Does not stimulate insulin production
    • Reduces insulin levels
  • Decreases hepatic glucose production (at higher dose)
  • Decreases triglyceride levels (decrease hepatic production and increase clearance)
• Indications (Type 2 Diabetes Only)
  • Monotherapy as adjunct to diet and exercise
  • Combination therapy
    • With Sulfonylureas (Pioglitazone & Rosiglitazone)
    • With Metformin (Pioglitazone)
    • With insulin (Pioglitazone)
• Dosing
  • Actos start 15-30 mg po qd, max dose 45 mg once a day
  • Avandia start 4 mg qd or divided bid, max dose 8 mg qd or divided bid.
• Considerations:
  • May take 4-12 weeks to see full effect
• Contraindications:
  • Known hypersensitivity
  • Clinical evidence of active liver disease or ALT>2.5 times upper limits normal (7-40 u/L)
• Precautions: Rosiglitazone
  • Check liver enzymes prior to start of therapy and then every 2 months for the first 12 months and periodically thereafter.
  • Use with caution in patient with edema
  • Mild LDL elevations seen in pre-marketing trials
• Precautions: Pioglitazone
  • Check liver enzymes prior to start of therapy and then every 2 months for the first 12 months and periodically thereafter.
  • Use with caution in patient with edema
• Precautions: Thiazolidinediones (all)
  • May cause resumption of ovulation in anovulatory women
  • May cause slight decrease in hemoglobin in first 4-12 weeks due to increased plasma volume
• Drug Interactions
  • Rosiglitazone (CYP 2C8 and to a smaller effect 2C9)
    • No effect on OC's
    • No effect on CYP 3A4 drugs
  • Pioglitazone (CYP 2C8 and 3A4)
    • Effect on OCs not yet studied
    • Caution with other 3A4 drugs
• Side Effects
  • Rosiglitazone
    • URI, Injury
    • More common in patients on combination therapies
  • Pioglitazone
    • URI, Headache, Sinusitis, Myalgia,
    • Edema more common in combined insulin treated patients
• Dosing
  • Rosiglitazone (Avandia)
    • Can be dosed with or without food
    • Start at 2mg bid OR 4 mg qd
    • Maximum dose 8mg/d (4mg bid dosing may be more effective)
  • Pioglitazone
    • Can be dosed with or without food
    • Initiate at 15 mg qd or 30 mg qd
    • Maximum dose 45 mg qd
    • Maximum dose in combination therapy trials was 30 mg qd

Comparing Thiazolidinediones
	Rosiglitazone (Avandia)	Pioglitazone (Actos)
LDL Cholesterol	Increase	Equal
Triglycerides	Equal	Decrease
HDL Cholesterol	Increase	Increase
Metabolism	2C8 & 2C9	2C8 & 3A4
Dosing	qd or bid	qd
Change in HbA1c	Decrease 0.9 - 1.5%	Decrease 1.0 - 2.6%

Meglitinides

• Repaglinide (Prandin)
• Oral Hypoglycemic Agent
• Effects:
  • Short acting insulin secretion – different than sulfonylureas
  • Stimulates release of insulin from pancreas
  • Increases insulin levels
  • Reduces fasting and postprandial hyperglycemia
• Indications: Type 2 diabetes (adults only) as an adjunct to diet and exercise
  • Monotherapy
  • Combination with Metformin
• Dosing:
  • If not previously treated with oral agents or if HbA1c < 8% the initial dose is 0.5 mg tid with each meal
  • HbA1c > 8% or switching oral agents, initially 1-2 mg with each meal
  • Combination with metformin: begin repaglinide dosing as in monotherapy if inadequate control with metformin or add metformin to repaglinide if inadequate control as monotherapy
• Considerations:
  • Always dose preprandially, 0-30 minutes before each meal
  • Maximum dose 16 mg/day
  • Dose 2, 3, or 4 times daily based on meal pattern
  • Dosing changes should be made based on fasting blood sugar (FBS) and HbA1c
  • Allow at least 1 week before dose adjustments
  • If meal skipped or added, skip or add a dose
  • Supplied in 0.5 mg (white), 1 mg (yellow), 2 mg (red) tablets
• Advantages:
  • Insulin release only at time of meals
  • Less hyperinsulinemia between meals which decreases risk of hypogylcemia
  • Reduces post prandial glucose spikes
  • Flexibility with meals
• Contraindications:
  • Diabetic ketoacidosis
  • Type 1 diabetes
  • Known hypersensitivity
• Precautions:
  • Hypoglycemia
    • Rates equal that of glyburide and glipizide
    • Must be taken with meal
    • More common in patients who have never taken oral agents or those with HbA1c < 8%
  • Patients with liver disease may have higher levels of repaglinide
• Drug Interactions:
  • Inhibitors of the cytochrome P-450 3A4 system may inhibit repaglinide metabolism causing increased repaglinide levels and effects ("azole" antifungal agents, erythromycin)
  • Inducers of the cytochrome P-450 3A4 system may inhibit repaglinide metabolism casing decreased repaglinide levels and effects (Thiazolidinediones, Rifampin, Barbiturates, Carbamazepine)
  • No relevant interactions with digoxin, warfarin, thoephylline, or cimetidine
• Side Effects: Hypoglycemia

Customizing Pharmacotherapy for Type 2 Diabetes: Summary Considerations

• Insulin resistance (triglycerides, HDL, B/P, etc.)
• Risks for hypoglycemia
• Risk for hypoxemia (and lactic acidosis)
• Co-existing conditions (CHF, liver disease, decreased kidney function, etc.)
• Costs/availability

Oral Agents Used in the Treatment of Type 2 Diabetes
Oral Agent	Primary Action	Metabolized	Side Effects	Dosing
Sulfonylureas	Increase insulin secretion by pancreas	Primarily liver, excreted by kidney	Hypoglycemia, rash, weight gain	1-2 times daily
Biguanides (Metformin)	Decreases hepatic glucose production	Not metabolized, eliminated by kidneys	Diarrhea, GI, rarely lactic acidosis	1-3 times daily with food
Alpha-Glucosidase Inhibitors (Acarbose, Miglitol)	Delays absorption of complex carbohydrates in intestines	Not absorbed systemically	Gas, cramping	1-3 times daily with the first bite of a meal
Thiazolidinediones (Actos, Avandia)	Reduces insulin resistance at cellular level	Liver	Few side-effects, possibly rare idiosyncratic liver damage	1-2 times daily
Meglitinides (Prandin)	Increases pancreatic insulin secretion	Liver (C P-450 3A4)	Hypoglycemia	2-4 times daily with each meal

Oral Agents Effects on Glycemia and Insulin
Class	IS	IR	HGP	Risk of Hypos*	HbA1c	Insulin Levels	TG Levels
Sulfonylureas	Increase	Equal	Equal	Yes	Decrease 1.0-1.5	Increase	Decrease/Equal
Biguanides	Decrease	Decrease/Equal	Decrease	No	Decrease 1.0-1.5	Decrease	Decrease
Alpha-Glucosidase Inhibitors	Decrease	Decrease/Equal	Equal	No	Decrease 0.5-1.0	Decrease (post-prandial)	Decrease/Equal
Thiazolidinediones	Decrease	Decrease	Decrease/Equal	No	1.0-1.5	Decrease	Decrease/Equal
Meglitinides	Increase	Equal	Equal	Yes	1.0-1.5	Increase	Decrease/Equal
* When used as monotherapy IS=Insulin Secretion IR=Insulin Resistance			HGP=Hepatic Glucose Output TG=Triglyceride

ADA Clinical Practice Recommendations online at: http://journal.diabetes.org/CareSup1Jan00.htm

References