DIABETES
April 1, 2000

New Drugs for Type 2 Diabetes

Sulfonylureas are among the least costly and most effective medications for the treatment of type 2 diabetes.

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.

Type 2 Diabetes Is Not Only a Disease of Carbohydrate Metabolism
Patients with type 2 diabetes often have many associated disorders, including hypertension (high blood pressure), obesity, hyperlipidemia (excess fat in the blood) and accelerated atherosclerosis (damaged arteries caused by fatty deposits). Diabetes may worsen these disorders. For this reason, it is important to treat both the diabetes and the associated disorders together. Treatment goals for hypertension and hyperlipidemia are now included in all ADA (American Diabetes Association) recommendations for diabetes management.

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.

Not by Drugs Alone
It must be remembered, even though the emphasis of this article is on drug treatments, that medications should never be used without non-drug therapies, such as diet, a regimen of physical activity and patient education. Newly diagnosed diabetic patients without severe symptoms should always try diet and exercise first. And even when drug treatment has begun, life-style changes and education remain an important part of managing diabetes.

Goals of Therapy
Careful control of blood sugar reduces the long-term effects of type 2 diabetes on the body's circulatory system. We have learned a great deal about this from two recent studies (the Diabetes Control and Complications Trial [DCCT] study and the U.K. Prospective Diabetes Study [UKPDS]). As a result of these important large-scale research studies, the ADA has set new therapeutic goals. These include a target level of 7% for HbA1c (glycated hemoglobin - a measure of blood glucose control that provides information about average glucose levels over months rather than minutes or hours, which is all the information that blood glucose levels can provide); 80 - 120 mg/dl (4.4-6.6 mmol/l) for fasting plasma glucose (FPG); and 100-180 mg/dl (5.5-10 mmol/l) for postprandial (after eating a meal) glucose.

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.

Table 1.
Classes of Agents Available for Treatment of Type 2 Diabetes

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

HGP, hepatic glucose production

Drugs that Promote the Body's Production of Insulin (Insulin Secretagogues)

Sulfonylureas
This class of agents was the mainstay of the treatment of type 2 diabetes for many years. They stimulate the body to produce, or secrete, more insulin. Other beneficial effects of the sulfonylurea class of drugs include suppression of glucose production in the liver and enhancement of the body's ability to dispose of excess glucose into fat and muscle tissue.

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.

Benzoic Acid Derivatives (Repaglinide)
Repaglinide stimulates insulin secretion in a different way from the sulfonylureas. It is rapidly absorbed and quickly metabolized in your body; this means that you will need three doses each day. For some patients, this presents an inconvenience but for others, with erratic lifestyles that lead them, occasionally, to miss meals, skipping repaglinide at the same time appears to be very effective.

Repaglinide seems to have little effect on lipids and can, like the sulfonylureas, cause weight gain and hypoglycemia.

Table 2.
List of Oral Agents

Class of Agent Generic Name Trade Name(s)
Sulphonylureas:
1st generation*
tolbutamide
chlorpropamide
tolazamide
Orinase®
Diabinese®
Sulphonylureas:
2nd generation
glyburide
glipizide
glimepiride
Diabeta®, Micronase®, Glynase®, Glucotrol®, Glucotrol XL®, Amaryl®
Benzoic Acid Derivatives repaglinide Prandin®
Biguanides metformin Glucophage®
Thiazolidinediones troglitazone
roziglitazone
pioglitazone
Rezulin®
Avandia®
Actos®
Alpha-glucosidase inhibitors acarbose
miglitol
Precose®
Glyset®

* This is not a complete list of 1st generation sulphonylureas. Their only current indication is cost. When costs of generic second generation sulphonylureas become low enough, there will not be an indication for first generation agents any longer in the treatment of diabetes.

Drugs that Reduce Glucose Production by the Liver

Metformin
Metformin is not a new medication, although it was only approved by the FDA for use in the United States in 1995. Its primary effect is to inhibit the liver's production of glucose and, possibly, to stimulate the process of transporting glucose into muscle, a process which requires insulin. Thus it only works when there is insulin around, for example in type 2 diabetes, but not type 1 diabetes, which is characterized by insulin deficiency. Exactly how metformin works is not well understood.

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.

Drugs that Help the Body Respond to Insulin (Insulin Sensitizers)

Thiazolidinediones
The thiazolidinediones (TZDs) enhance insulin action in muscle, fat and other tissues and are known as insulin sensitizers. They require the presence of insulin in order to work, so TZDs are not indicated for type 1 ("insulin dependent diabetes") and certain other varieties of diabetes.

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 (Rezulin®) 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.

Drugs that Reduce Postprandial Glucose Concentrations

Glucosidase Inhibitors
After you eat, the food is digested, then passes into the bloodstream and, thus, the level of sugar in the blood rises. Glucosidase inhibitors act in the intestine to block the action of enzymes that are responsible for breaking down complex carbohydrates into simple sugars. This delayed breakdown of carbohydrates helps slow down their absorption into the bloodstream and, thus, slow down the increase in blood glucose levels after a meal.

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.

Combination Therapy
As mentioned above, primary therapy can begin with a sulfonylurea or metformin and the goal of therapy is to achieve ADA guidelines for glucose control. If treatment with one drug fails to achieve this goal, doctors may reevaluate your diet, exercise and knowledge about diabetes, and they may add another medication.

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:
  1. How poor is the glucose control?
  2. The patient's age and the presence of long-term complications of diabetes.
  3. Patient preference (insulin, which needs to be injected, versus a second or third oral agent).
  4. Other diseases (e.g., kidney disease will affect the decision to use metformin, liver disease for TZDs).
  5. 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.

Future Antidiabetic Medications
Many pharmaceutical companies are working to produce new drugs for type 2 diabetes. These include novel classes of drugs as well as new insulin sensitizers and new stimulators of insulin secretion. One example, which is expected to be available shortly, is nateglinide (Starlix®), a rapid-onset, short-duration drug that is similar to repaglinide in effect, though quite different chemically. This drug is an effective stimulator of insulin secretion, is used prior to meals and may be prove to be useful as primary therapy.
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