Compiled by: Eric Brandt, B.Sc. Pharm (Pharmacist). updated July 3, 2001
The body derives most of its energy from glucose which we consume or from glucose which the body itself makes from other foods we eat. The pancreas produces a hormone called insulin which enables the body to utilize the glucose for energy or store it for later use. Absence of sufficient insulin to meet the needs of the body results in a collection of abnormalities which we call Diabetes Mellitus (DM).
There are two types of diabetes mellitus: type I usually occurring in people younger than 40 and most commonly between the ages of 10 and 16. This type of diabetes is sometimes called Insulin Dependent Diabetes Mellitus (IDDM), or Juvenile Onset Diabetes Mellitus (JODM). It usually develops rapidly when insulin secreting cells in the pancreas are destroyed. IDDM is treated with insulin injections.
Type 2 diabetes mellitus is the other major form of the disease. It usually occurs in middle aged and older adults. It is more common among overweight people who eat large amounts of sugary foods. Type 2 diabetes is sometimes referred to as Non Insulin Dependent Diabetes Mellitus (NIDDM) or Maturity Onset Diabetes Mellitus (MODM). It is thought that in the older NIDDM patient insulin is produced but not in sufficient quantities. It is also thought that the body is less sensitive to the produced insulin, resulting in a less efficient response.
There seems to be a genetic predisposition to both types of diabetes mellitus.
Many type 2 overweight diabetics are able to control their blood sugar level by reducing excess weight and by controlling their sugar intake. Other type 2 diabetics require drug therapy in addition to dietary measures to control their condition.
It is important to control the diabetic state in order to prevent serious long term risks. We know that if uncontrolled, diabetes increases a person's risk to develop heart disease, stroke, circulatory problems, eye and kidney damage, impaired wound healing, increased susceptibility to infections and peripheral nerve damage.
The oral anti-diabetic agents currently available are classified according to their chemical structure: sulphonylureas, metformin and acarbose.
| Generic name | Brand name |
|---|---|
| Acetohexamide | Dimelor |
| Chlorpropamide | Diabinese |
| Tolbutamide | Orinase, Mobenol |
| Glyburide | Diabeta, Euglucon |
| Gliclazide | Diamicron |
The sulphonylureas differ from each other in how long they take to start working, the duration of their effectiveness, and the amount of each required to produce roughly equivalent anti-diabetic effect. See table 2.
These drugs do not lower blood glucose on their own. They require some functioning pancreatic cells in order to be effective. We do not know exactly how these drugs achieve their anti-diabetic effect, but it is thought that they stimulate the release of insulin and/or that they may increase the body's sensitivity to insulin.
| Drug | Hours to start working | Hours of effectiveness | Usual daily dosage |
|---|---|---|---|
| Acetohexamide | one | 12-24 | 250 mg-1,500 mg |
| Chlorpropamide | one | up to 60 | 250 mg - 500 mg |
| Tolbutamide | 1-1.5 | 6-12 | 500 mg- 2,000mg |
| Glyburide | 1-1.5 | 18-24 | 2.5 mg-20 mg |
| Gliclazide | 1-1.5 | 18-24 | 40 mg- 320mg |
Metformin is chemically unrelated to the sulphonylureas. It belongs to a class of drugs called biguanides. Like the sulphonylureas it requires the presence of some insulin. The exact mechanism of action of metformin has not been clearly established. There are several proposed mechanisms by which metformin may lower blood glucose: reducing the amount of glucose made by the liver, decreasing or delaying the absorption of glucose from the intestine, increasing body utilization of glucose, and increasing the body's sensitivity to insulin.< /p>
Metformin may be used alone or in combination with one of the sulphonylureas. Metformin starts to exert its anti-diabetic effect one hour after ingestion and the effect lasts from 6 to 12 hours. The usual dose range is 500 mg to 750 mg up to three times a day.
The most common side effeects of anti-diabetic drugs are: loss of appetite, nausea, vomiting and stomach upset
Less common side effects associated with these drugs are: abnormally low blood sugar level, yellowing of skin and eyes, itching or rash
Metformin is less likely to cause abnormally low blood sugar level than the sulphonylureas.
Older adults, especially those with reduced kidney function are more sensitive to the blood sugar lowering effects of these drugs because they do not eliminate them from the body as efficiently as younger patients with normal kidney function.
Acarbose
Acarbose (trade name Prandase) was introduced to the Canadian market in 1995. It represents the first new breakthrough in treatment of type 2 diabetics in 40 years. It is classified as an alpha-glucosidase inhibitor. Acarbose has a chemical structure similar to natural carbohydrate. Unlike the sulphonylureas and metformin, it does not enhance insulin secretion. The anti-diabetic action of acarbose results from its binding with pancreatic enzymes which normally degrade starch, sucrose and maltose to simpler sugars (mainly glucose) which are then absorbed. This results in inhibition of those enzymes and consequent delaying of glucose absorption and smoothing and lowering of blood glucose levels following meals.
Acarbose is indicated as an adjunct to prescribed diet and can be used with other oral anti-diabetic drugs.
Because of its mode of action, acarbose is not likely to cause abnormally low blood sugar.
The tablets should be taken orally three times a day with the first bite of each main meal.
The most common side effects while taking Prandase are gastrointestinal in nature, such as flatulence (gas) and abdominal discomfort. It is also possible that softer stools may be experienced or even diarrhea- particularly after a meal containing foods with sucrose (ordinary sugar). Normally these symptoms will diminish with continued treatment. Antacids have no beneficial effects in relieving these symptoms.
Acarbose (Prandase) should not be taken by patients with inflammatory bowel disease, colonic ulceration, partial intestinal obstruction, or patients who are predisposed to intestinal obstruction. In addition Prandase should not be taken by patients who have chronic intestinal diseases associated with marked disorders of digestion or absorption. The drug should not be taken by those patients who suffer from states which may deteriorate as a result of increased gas formation in the intestine, e.g. larger hernias.
Rapaglinide
Repaglinide (trade name: Gluconorm by Novo Nodisk) is a short acting insulin secretagogue, chemically unrelated to oral sulfonylureas. It lowers fasting and postprandial blood glucose levels by stimulating the release of insulin from the beta cells in the pancreas. Beta cells must be functioning for repaglinide to exert its effect. Repgalinide is quickly absorbed following oral administration, with peak plasma levels occuring within one hour. The drug is completely metabolized by the liver to inactive metabolites which are excreted primarily in the feces. The elimination half life is approximately one hour.
There is no fixed dosage regimen for repaglinide. The recommended starting dose is 0.5 mg with each meal for previously untreated patients or those with glycosylated hemoglobin (HbA1c) of <8%. Doses are usually taken within 15 minutes of a meal, but cn be taken at any point starting from 30 inutes before the meal , up to immediately prior to the meal. For patients previously treated with blood glucose-lowering drugs and those with HbA1c >8% the initial dose is 1 or 2 mg with each meal. Dosage adjustments are made according to response at one week intervals etween each dose change. The maximum individual dose is 4 mg. The maximum daily dose is 16 mg. If a meal is missed or delayed or added, the dose of repaglinide should also be missed, delayed or added accordingly.
The most common adverse effect with repaglinide is hypoglycemic reaction. This reaction is more likely to occur in patints with liver or adrenal or pituitary disease, as well as in elderly , debilitated or malnourished patients. Hypoglycemic reactions are also more likely to occur when calorin intake is deficient, when meals are skipped, after strenuous or prolonged exercise,, when alcohol is ingested, or when more than one hypoglycemic agent is being used.
Drug interactions: Erythromycin, ketoconazole and miconazole may inhibit repaglinide metabolism. Rifampin, carbamazepine and barbiturates may induce repaglinide metabolism
Thiazolidinediones
The first agent in this class was troglitazone, Rezulin, manufactured by Parke-Davis. This drug never made it to Canada. Subsequent to its introduction into the market there had been more than 60 reports of liver toxicity in patients taking this drug. In march 2000 the US Food and Drug Administration had requested Parke-Davis to remove troglitazone from the market.
Recently, two newer agents in this drug class were approved and became available here in Canada. These drugs are: rosiglitazone (Avandia) and pioglitazone (Actos).
A majority of the data reporting the efficacy of this class comes from studies with troglitazone, although results from more recent studies with the newer agents (rosiglitazone and pioglitazone) demonstrate similar properties. The thiazolidinediones work by enhancing insulin sensitivity in both muscle and fatty tissue and to a lesser extent by inhibiting liver production of glucose.
These agents have a notable effect on improving insulin resistance, particularly when used in combination with other antidiabetic drugs, but have no effect on insulin secretion.
Monotherapy with these agents has been associated with a 0.5 to 1.5 percent reduction in HbA1c levels and 25 to 50 mg per dL (1.4 to 2.8 mmol per L) reduction in fasting plasma glucose levels. As a class, the thiazolidinediones have also been shown to alter lipid profiles in patients with type 2 diabetes. Results from studies with troglitazone consistently show a decrease in triglyceride levels in some cases by as much as 33 percent. The effects on high density lipoprotein (HDL) cholesterol levels have been either favorable or neutral, while some studies report an increase in total and LDL cholesterol levels. Newer data reveal that as monotherapy, rosiglitazone is associated with increases in total, LDL and HDL cholesterol levels and either no change or increases in triglyceride levels. Patients treated with pioglitazone have displayed mean decreases in triglyceride levels, mean increases in HDL cholesterol levels, and no consistent mean changes in LDL and total cholesterol levels.
Because these agents do not increase insulin secretion, hypoglycemia does not pose a risk when thiazolidinediones are taken as monotherapy. Significant weight gain has been reported with all three agents. The thiazolidinediones are relatively safe in patients with impaired renal function because they are highly metabolized by the liver and excreted in the feces; however, caution should be used in patients with liver dysfunction because troglitazone and its metabolites have been shown to accumulate in this setting.
Mild to moderate edema has been reported in 5 to 7 percent of patients treated with rosiglitazone and pioglitazone. The increase in plasma volume is of concern in patients with congestive heart failure particularly those with New York Heart Association class III or IV functional status. The use of thiazolidinediones should be avoided in these patients.
Of greatest concern are the reports of adverse effects on the liver with troglitazone. This reaction is initially characterized by increased serum transaminase levels, which in some cases progressed to hepatitis, liver failure and death. Although results from pre-marketing trials revealed no evidence of liver toxicity with the newer agents (rosiglitazone and pioglitazone), two recent case reports demonstrated that rosiglitazone may be associated with liver failure following just 14 days of therapy, although a true cause-and-effect relationship has not been established.
The manufacturers recommend that these agents not be prescribed for patients with serum transaminase levels that exceed 2.5 times the upper limit of normal
It is recommended that serum transaminase levels be monitored every other month for the first year in all patients receiving a thiazolidinedione. Following one year of therapy with the newer agents, the incidence of serum transaminase elevations has been reported to be similar to placebo.
The time to achieve a desired effect with the thiazolidinediones is somewhat longer than the other classes of hypoglycemic agents discussed thus far. Intervals of at least three to four weeks should be allowed before increasing the dosage of these agents. Smaller dosages can be initiated if used as part of a combination regimen with a sulfonylurea or a sulfonylurea plus metformin.
In patients receiving insulin therapy, the addition of a thiazolidinedione has resulted in significant reductions in daily insulin requirements.
There are a number of drugs, prescription and non-prescription, which interfere with the actions of the anti-diabetic drugs reviewed here. Some drugs which interfere with these anti-diabetic agents are: Aspirin (ASA), Dilantin (phenytoin), Coumadin (warfarin), and some diuretics (water pills). Patients on these drugs must be closely monitored by their doctor. Interaction with alcoholic beverages cause flushing of the face and body and may sometimes also cause palpitations. Remember to always check with your doctor or pharmacist before purchasing any non-prescription medication. Always keep a list of all the medications you take to show any new doctor, dentist or specialist you see.