Diabetes Outreach Network
QUICK REFERENCE GUIDE TO DIABETES FOR HEALTH CARE PROVIDERS

5. Pharmacological Treatment of Diabetes

Pharmacological therapy is started after 4-12 weeks if an individualized meal plan, activity, and weight loss trial (if needed) have failed to control blood glucose. If the blood glucose remains above 126 mg/dl fasting and over 200 mg/dl 1-2 hours postprandial, pharmacological treatment will be initiated. Patients with extremely high blood glucose and symptoms such as polyuria, and polydipsia, may need insulin to be started immediately. Insulin may be needed for a short period of time or indefinitely. A review and alteration of the other medications the patient is taking may help to control blood glucose; hyperglycemia may result from nicotinic acid, thiazide diuretics (large doses), beta blockers, Indocin, Dilantin, corticosteroids and fertility agents.

There are currently 6 classifications of oral therapy for type 2 diabetes as follows:

• Sulfonylureas
• Benzoic Acid Derivatives
• D-Phenylalanine Derivatives
• Biguanides
• Alpha Glucosidase Inhibitors
• Thiazolidinediones

Medication Failures

• After 5 years, approximately 50% of patients will require medication adjustments.
• Combination therapies can be tried before discontinuing the failed drug (i.e. add metformin if person has failed with sulfonylurea to control blood glucose).
• If combination therapy fails to control blood glucose, insulin is the next line of treatment - see Insulin and Type 2 Diabetes.

Sulfonylureas

• Stimulate the pancreas to make more insulin. Over time, the body’s ability to make insulin may lessen. If this happens, these drugs lose their ability to control blood glucose.
• Fasting plasma glucose 126-200 mg/dl may respond to monotherapy along with dietary management.
• If a sulfonylureas alone fails to control blood glucose, combination therapy or insulin may be used to achieve blood glucose control.
• Fasting plasma glucose 200-275 mg/dl may need 2 agents or insulin.

  1st Generation

• Tolbutamide (Orinase)
• Tolazamide (Tolinase)
• Chlorporpamide (Diabinese)

  2nd Generation

• Glyburide (DiaBeta, Micronase, Glynase PresTabs)
• Glipizide (Glucotrol, Glucotrol XL)
• Glimepiride (Amaryl)

  Side Effects

• Hypoglycemia
• Weight gain
• Skin Rashes
• GI (5%)
• Hepatic changes (rare)
• Hematologic changes (1st generation drugs)

  Contraindications

• Type 1 diabetes
• Pregnancy and lactation
• Diabetic Ketoacidosis
• Severe renal or hepatic disease
• Elderly, debilitated or malnourished persons
• Allergy to sulfa
• Serious illness/severe infection
• Surgery, trauma or severe metabolic stressor

  Dosing

• Start at lowest possible dose. (See Oral Antidiabetes Medications for actual doses.)
• Increase every 1-2 weeks until glucose control or maximum dose has been reached
• Longer-acting agents may not be recommended for the elderly.
• Renal insufficiency may require dose reduction.
• There is no benefit to using two sulfonylureas (i.e. Diabeta and Glucotrol) together.

  Candidates for Initial Use

• Type 2 diabetes, no dyslipidemia, not overweight, and fasting plasma glucose > 20 mg/dl above target

Benzoic Acid Derivative

Repaglinide (Prandin)

• Enhances insulin secretion. Is a short-acting agent. The amount of repaglinide-induced insulin release depends on the blood glucose level. Insulin release diminishes as the glucose level declines.
• Has the potential to cause hypoglycemia, but to a lesser extent than sulfonylureas.
• If a meal is skipped, the dose is skipped; if a meal is added, a dose is added for that meal.
• May be taken with decreased kidney function.

  Precautions

• Longer half-life may be found with antifungals, erythromycin and clarithormycin.
• Accelerated repaglinide metabolism and shortened drug effect may be found with use of rifampin, phenobarbital, carbamazepine, and troglitazone.

  Side Effects

• Hypoglycemia (16-31%)
• GI (4%)
• Upper respiratory infections
• Back pain
• Headache

  Contraindications

• Type 1 diabetes
• Pregnancy and lactation
• Diabetic Ketoacidosis
• Impaired hepatic function
• Elderly, debilitated or malnourished persons
• Surgery, trauma or severe metabolic stressor
• Serious illness/severe infection

  Dosing

• Is available in 0.5 mg, 1 mg and 2 mg dosage units. Maximum dose is 16 mg. per day.
• Take with meal.
• Number of daily doses is determined by the number of meals eaten.
• Initial dose for clients not previously treated with BG lowering agents: 0.5 mg/meal
• Initial dose for clients previously treated with BG lowering agents or HbA1C > 8%: 1-2mg/meal

  Candidates for Initial Use

• Type 2 diabetes, no dyslipidemia, with or without renal failure, not overweight, and fasting plasma glucose > 20 mg/dl above target

D-Phenylalanine Derivatives

Nateglinide (Starlix)

• Is very rapid-acting.
• Stimulates insulin secretion when needed (postprandial), then allows insulin concentrations to return to baseline.
• If a meal is skipped, the dose is skipped; if a meal is added, a dose is added for that meal.

  Side Effects

• Hypoglycemia (2.4%)
• Dizziness (3.6%)
• Weight gain of < 1 kg

  Contraindications

• Type 1 diabetes
• Pregnancy and lactation
• Diabetic Ketoacidosis

  Dosing

• Is available in 60 mg and 120 mg tablets.
• Typical dose: 120 mg taken just before meals. (60 mg tid can be used for those near their HbA1C goal)
• Not recommended for combination with a sulfonylurea or Prandin.

  Candidates for Initial Use

• Type 2 diabetes with the ability to produce insulin, significant postprandial hyperglycemia not controlled by nutrition therapy and exercise.

Biguanides

Metformin (Glucophage, Glucophage XR)

• Primary action is decreasing glucose output from the liver. Does not stimulate insulin release.
• Controls blood glucose without causing hypoglycemia or weight gain in most people. A 2-5 kg weight loss is typical.
• Can be used as monotherapy if diet alone does not control blood glucose. Can be used in combination therapy when euglycemia is not achieved with the sulfonylurea alone.
  • Fasting plasma glucose 126-200 mg/dl may respond to monotherapy along with dietary management.
  • Fasting plasma glucose 200-275 mg/dl may respond to a combination therapy or insulin.
• Studies show a decrease in triglycerides (16%), LDL-cholesterol (8%) and total cholesterol (5%); along with an increase in HDL-cholesterol (2%).
• Educate patient to immediately report symptoms associated with lactic acidosis (severe weakness, cold, labored breathing, stomach pain, light headed or irregular heart rate).
• Evaluate kidney and liver (LFT) before initiating metformin. Test creatinine and LFTs every 6-12 months while on metformin therapy.

  Side Effects

• Most common: GI (abdominal bloating, nausea, cramping, diarrhea, feeling of fullness)
• Minor effects: agitation, headache, metallic taste
• Lactic acidosis (rare)
• May reduce B12 levels (rare)

  Contraindications

• Type 1 diabetes.
• Pregnancy and lactation.
• Acute or chronic of lactic acidosis.
• Hepatic dysfunction
• Renal dysfunction with serum creatinine >1.5 mg/dl for men and >1.4 mg/dl for women.
• Over age 80
• History of alcoholism or binge drinking
• Metformin should be temporarily discontinued in any situation that predisposes the individual to acute renal dysfunction including:
  • Cardiac collapse
  • Acute myocardial infarctions
  • Acute exacerbated congestive heart disease.
  • Use of iodinated contrast media (withhold 48 hours before and after test)

  Dosing

• Metformin (Glucophage) is available in 500 mg and850 mg dosage units. Glucophage XR is available in a 500 mg dosage unit.
• Start at 500 mg per day or 500 mg bid (XR: 500 mg with evening meal)
• Increase by 500 mg per day every 2 weeks (1 week for XR) up to a maximum effective dose of 2000 mg. (Usual dose 1500-2000 mg per day split into two or three doses - 850 mg tablet in the AM and another in the PM.)

  Candidates for Initial Use

• Type 2 diabetes, dyslipidemia, obesity or genetic factors favoring insulin resistance, and fasting plasma glucose > 20 mg/dl above target

Alpha Glucosidase Inhibitors

Alpha (Precose) and Miglitol (Glyset)

• Delays carbohydrate digestion and slows absorption. Does not cause hypoglycemia.
• Approved for use in type 2 diabetes to treat postprandial hyperglycemia.
• Generally will not be effective in the treatment of significant fasting hyperglycemia.
• Can decrease postprandial blood glucose by about 50 mg/dl and HbA1c by approximately 0.5-1%. (Higher blood glucose levels can decrease more.)
• If hypoglycemic reactions occur, oral glucose (not sucrose) must be used for treatment.
• Should not be used if the patient is using lispro (Humalog) or Novolog (Aspart) insulin--mechanism of action is similar. Should also not be used with metformin--severe GI side effects may occur.
• Check serum transaminase level every 3 months during the first year and then periodically. If elevated, discontinue acarbose. (Liver abnormalities do not seem to be a concern with miglitol.)
• May be used alone or in combination therapy

  Side Effects

• Most common: GI (abdominal pain, diarrhea, flatulence)
• Increased serum AST or ALT (Acarbose doses > 200 mg tid)

  Contraindications

• Safety not tested for pregnancy or lactation
• Chronic intestinal problems or diseases present (inflammatory bowel disease, colonic ulceration, obstructive bowel disease and gastroparesis).
• severe liver and renal disease (creatinine > 2.0).

Dosing and Administration

• Precose and Glyset are each available in 25 mg, 50 mg and 100 mg tablets.
• Given with the first few bites of major meals.
• Precose: starting dose 25 mg qd (to decrease side effects), add second dose after 2 weeks and third dose after an additional 2 weeks. Increase to 50 mg tid for 4-8 weeks . Maintenance dose of 50-100 mg tid.
• Glyset: starting dose of 25 mg tid for 4-8 weeks, then 50 mg tid for 3 months. Increase to 100 mg tid if tolerated and needed.
• Maximum doses (arcarbose)
  • patients < 60 kg: 50 mg tid
  • patients > 60 kg: 100 mg tid
• Maximum dose (miglitol):  100 mg tid

Candidates for Initial Use

• Type 2 diabetes, dyslipidemia, obesity, and significant postprandial hyperglycemia

Thiazolidinediones

Pioglitizone (Actos) and Roisglitizone (Avandia)

• Decreases insulin resistance and increases glucose uptake in muscle and adipose tissue.
• Useful in patients with renal dysfunction or other conditions in which metformin is contraindicated.
• Generally well tolerated.

  Precautions

• Liver toxicity has been reported with the use of Rezulin. It was withdrawn from the U.S. market on 3/21/00.
• Liver function tests should occur with Actos and Avandia. Check serum transaminase levels (ALT) prior to starting therapy, every 2 months during the first year, and then periodically.
• Do not use if ALT exceeds 2.5 X upper limit of normal or if active liver disease is present.
• If ALT exceeds 3 X upper limit of normal during treatment, recheck as soon as possible. Discontinue drug if ALT remains > 3 X upper limit of normal.
• Check liver function immediately if signs of hepatic dysfunction occur (nausea, vomiting, abdominal pain, fatigue, anorexia)

  Side Effects

• Increased hepatic enzymes
• Weight gain
• Plasma volume expansion
• Edema
• May make oral contraceptive less effective

  Contraindications

• Pregnancy or lactation
• Children
• Hepatic dysfunction
• NYHA Class III or IV Heart Failure
• Pre menopausal anovulatory women with insulin resistance.

  Dosing - Actos

• Approved for monotherapy or in combination with sulfonylurea, metformin or insulin
• Available in 15 mg, 30 mg and 45 mg tablets.
• Initial starting dose in monotherapy or combination therapy is 15 mg or 30 mg once daily, taken without regard to meal.
• Maximum dose is 45 mg once per day
• If used with insulin, insulin may need to be decreased by 10-25% if patient reports hypoglycemia.
• Sulfonylurea dose may need to be lowered if hypoglycemia occurs.
• Some studies showed a 5-26% decrease in triglycerides and a 6-13% increase in HDL-cholesterol.

Dosing Avandia

• Approved for monotherapy or for use with sulfonylurea, metformin or insulin
• Avandia is available in 2 mg, 4 mg and 8 mg tablets.
• Usual starting dose is 2 mg/day - single dose or divided into 2 doses/day.
• Max dose 8 mg/day. 4 mg bid is more effective than 8 mg once a day.
• Studies show small increases in HDL-cholesterol and LDL-cholesterol.

Candidates for Initial Use

• Type 2 diabetes, obesity or genetic factors favoring insulin resistance, and fasting plasma glucose > 20 mg/dl above target

Combination Therapy

Glucovance (glyburide/metformin)

• Available in 1.25/250 mg, 2.5/500 mg and 5/500 mg dosage units
• Side effects similar to those noted for glyburide and metformin.
• Contraindicated in those populations not indicated for use of gyburzide and metformin.

Metaglip (glipizide/metformin)

• Available in 2.5/250 mg and 2.5/500 mg dosage units
• Side effects similar to those noted for glipizide and metformin.
• Contraindicated in those populations not indicated for use of glipizide and metformin.

AvandaMet (Avandia/metformin)

• Available in 1/500 mg, 2/500 mg and 4/500 mg dosage units
• Side effects similar to those noted for rosiglitazine (Avandia) and metformin.
• Contraindicated in those populations not indicated by use of rosiglitazine (Avandia) and metformin.

Candidates for Combination Therapy

• When other therapies reach maximum doses and target BG levels not met (fasting BG > 140 mg/dl, postprandial BG > 180 mg/dl, HbA1C > 7-8%).

Oral Antidiabetes Medications