Oral Agents for Diabetes Type 2
by Tom Bartol, RN-C, MN, FNP, CDE

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


Last updated: December 1, 2000


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