Until recently, there were few medications (only sulfonylureas or insulin) available for the treatment of type 2 diabetes (also known as non-insulin dependent or adult-onset diabetes). But today, doctors have a wide variety of new types of drugs to help you regulate your blood glucose (sugar). In this article, we will look at all these medications and describe how they work.
Although we have little understanding of the underlying causes of type 2 diabetes, we now know that there are many different reasons why those who suffer from type 2 diabetes cannot control their blood sugar. Some do not produce enough insulin, the hormone that regulates blood sugar. Others produce enough insulin but are somehow resistant to its action. It is also known that the livers of patients with type 2 diabetes produce excess glucose and that this, too, can contribute to high blood glucose levels.
The presence of these associated disorders needs to be considered when choosing antidiabetic medications. A prime example is associated hyperlipidemia. Some anti-hyperglycemic agents, i.e., drugs that bring down blood glucose levels, also have beneficial effects on lipid (fat) disorders and may, therefore, be the best choice for patients who suffer from both conditions.
When you start on an oral drug treatment, it is important that you see your doctor at least every 2-4 weeks, so you can quickly be placed on the best dose of the medicine. Frequent visits, at the start of treatment, may, if necessary, also help the doctor determine whether another medication should be added without delay.
|Mechanism of Action||Class of Agent||Indication for Use|
|Stimulates insulin secretion||Sulphonylureas
Benzoic Acid Derivative
|Primary or secondary Rx|
|Suppresses HGP*||Biguanides||Primary or secondary Rx|
|Insulin sensitizer||Thiazolidinediones||Secondary Rx|
|Reduces postprandial plasma glucose excursion||Alpha-glucosidase Inhibitors||Secondary treatment|
|Insulin replacement||Insulin/insulin analogues||Failure of oral agents|
Sulfonylureas remain the most popular group of medications today. In part, this may be a function of physicians' habits but an important factor is their low cost. Many types of sulfonylureas are now generic and are among the cheapest medications available for the treatment of diabetes.
A drawback of sulfonylureas is that, on average, they lose effectiveness for 44% of patients within six years of beginning their use. Individual patients may have a more prolonged course of successful sulfonylurea treatment and others may need supplements even earlier than six years. Failure occurs more rapidly in younger, more hyperglycemic individuals and in those with lower insulin secretion at the start of treatment. While this may sound like a high rate of failure, it is important to remember that some of the newer drugs have not been in use for very long and we don't yet know how effective they are long-term. No matter how long you benefit from a particular oral agent without side effects, it is worth the time gained because it delays dealing with the inconvenience of using insulin. Furthermore, when used together with other drugs (see below), even though the sulfonylurea seems to have lost its effectiveness, the other drugs will work better in combination than on their own.
Hypoglycemia and weight gain are the two most frequent side effects of these drugs. An early study, the UGDP (University Group Diabetes Program), published in the 1970s, also raised the possibility that sulfonylureas might make heart disease worse. However, the UKPDS study, mentioned earlier, found that sulfonylureas are no more likely to increase coronary artery disease than any of the other agents tested (insulin and metformin), so the jury is out with respect to heart disease. We do know, however, that sulfonylureas have little or no effect on blood lipid concentrations.
Repaglinide seems to have little effect on lipids and can, like the sulfonylureas, cause weight gain and hypoglycemia.
|Class of Agent||Generic Name||Trade Name(s)|
|Diabeta®, Micronase®, Glynase®, Glucotrol®, Glucotrol XL®, Amaryl®|
|Benzoic Acid Derivatives||repaglinide||Prandin®|
Metformin can be used as a first line of therapy. It is useful for patients who are obese because it does not cause the weight gain seen with sulfonylureas; it may even bring about some degree of weight loss. Metformin is also as capable as the sulfonylureas in reducing HbA1c. An additional benefit of metformin is its positive effect upon lipid metabolism — it reduces blood triglyceride and LDL (the "bad") cholesterol levels by about 10% and also lowers fatty acids.
Side effects can be a problem with metformin. Up to 30% of patients develop gastrointestinal complaints, though these may be mild and temporary, especially if dosages are brought up slowly. The largest concern with metformin is the potential to produce a build up of lactic acid. However, this is a very rare side effect of the drug, particularly if care is taken not to prescribe metformin when it is contraindicated. Contraindications for this drug include evidence of kidney disease, significant liver disease, chronic alcoholism or congestive heart failure. Hypoglycemia and, as mentioned above, weight gain, are not on the list of metformin's side effects.
TZDs are effective in reducing HbA1c. They are also effective in combination with either sulfonylureas or metformin. Compared to other drugs, it takes a patient a long time to see the benefits of the TZDs. For this reason, doses should not be increased until after 4-6 weeks, the time it normally takes for maximal biological effect to occur. About 25% of patients do not respond to TZDs. Some TZDs also have beneficial effects on blood lipids. Troglitazone has a lipid lowering effect and increases HDL, or high-density lipoprotein ("the good cholesterol"). Pioglitazone also decreases triglycerides.
The major side effect, seen with troglitazone, the first TZD to be approved by the FDA, is liver damage. The effects observed range from an elevation in liver enzymes, which is reversible, to liver failure, which has caused death in a small number of patients. Because of this dangerous side-effect, the FDA, in March 2000, removed troglitazone (RezulinÃƒÆ’Ã¢â‚¬Å¡Ãƒâ€šÃ‚Â®) from the market. Two other members of the TZD class that have recently been approved by the FDA, rosiglitazone and pioglitazone, do not appear to cause liver damage. However, the FDA requires regular monitoring of liver enzyme levels with these drugs as well. Other side effects of TZD are mild elevations of LDL (the "bad") cholesterol and fluid retention — if you have heart trouble, TZDs may not be a good choice. TZDs do not cause hypoglycemia when used alone.
These medicines are not usually used for primary therapy unless a patient appears to have large increases in blood glucose after meals ("postprandial"). Glucosidase inhibitors are most useful in combination with other drugs.
Gastrointestinal side effects are common, affecting up to 30% of patients. Bloating, flatulence, diarrhea and abdominal discomfort and pain are the major complaints. However, these side effects can be reduced by eating less carbohydrates in the diet. Hypoglycemia is not often seen but, if the patient develops low blood glucose levels, he/she must be treated with glucose, not complex carbohydrates. This is because the action of these drugs, which prevent breakdown of complex carbohydrates in the intestine, will be unable to rapidly correct blood glucose concentrations. Weight gain does not occur with these drugs.
If treatment with two drugs fails, your doctor will have to determine whether or not to add another medication. The major decision is whether to start insulin at this point or, instead, try a different oral medication. This decision should be guided by the following considerations:
- How poor is the glucose control?
- The patient's age and the presence of long-term complications of diabetes.
- Patient preference (insulin, which needs to be injected, versus a second or third oral agent).
- Other diseases (e.g., kidney disease will affect the decision to use metformin, liver disease for TZDs).
- Cost. This will play an important role since there is a wide range of costs for the medications reviewed here. In general, the most recent drugs are the most costly and insulin, depending on dosage, is cheaper than the newer drugs.