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Diabetes - type 2

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of type 2 diabetes.

Alternative Names

Type 2 diabetes; Maturity onset diabetes; Noninsulin-dependent diabetes

Medications

The American Heart Association now recommends that patients should aim for the following test results for intensive control of glucose levels:

• Fasting plasma glucose concentrations below 110 mg/dL.
• Glycolated hemoglobin (HbA1c) levels of less than 7%. Controlling HbA1c is the most important factor for reducing the risk of complications in patients with diabetes. According to one 2000 study, a 1% reduction in people with elevated glycolated hemoglobin levels lowers the risk for complications by 21%.

Evidence clearly supports strict glycemic control for reducing complications in the nervous system and blood vessels that occur in both type 1 and type 2 diabetes. Research shows that tight glucose control can help prevent heart disease and complications.

It may be difficult for patients with type 2 diabetes to control their blood sugar levels--particularly if they are overweight. Metformin (Glucophage), an oral anti-hypoglycemic drug, helps control blood glucose levels, does not produce weight gain, and also has heart benefits. In comparison with other diabetic drugs, including insulin, it is the only drug proven to improve survival rates. A number of other oral drugs are also available that are beneficial, alone or in combinations. Insulin therapy may eventually be required when natural insulin reserves become depleted.

Managing risk factors for heart disease and stroke, particularly strict control of blood pressure, may be more important for improving survival than strict control of blood glucose levels for some patients. Such goals also seem to be more attainable for many patients with type 2 diabetes.

Oral Anti-Hyperglycemic Drugs. Many oral anti-hyperglycemic drugs are available to help patients with type 2 diabetes control their blood sugar levels. Most of these drugs are aimed at using or increasing sensitivity to the patient's own natural stores of insulin. Metformin is the only drug to date that achieves lower mortality rates:

• Biguanides (metformin). Metformin increases tissue sensitivity to available insulin. Metformin also has beneficial effects on cholesterol, blood pressure, and clotting factors. It does not cause weight gain or hypoglycemia. Metformin produces lower mortality rates than other drugs, including insulin, and should be considered as first-line therapy for most patients with type 2 diabetes.
• Sulfonylureas (glyburide, glipizide, and glimepiride). Stimulate insulin secretion.
• Meglitinides (repaglinide, nateglinide). Stimulate insulin secretion. These newer drugs are better than sulfonylureas in controlling glucose spikes after meals.
• Thiazolidinediones (pioglitazone and rosiglitazone). Reduce insulin resistance. These drugs improve cholesterol levels and may reduce the risk for blood clots. However, they can cause swelling from fluid build-up, which can worsen heart failure or even possibly precipitate it. They also may injure the liver.
• Alpha-glucosidase inhibitors (acarbose and miglitol). Slow intestinal absorption of carbohydrates. Have only modest effects on diabetes and have gastrointestinal side effects.

Combinations of these drugs, particularly with metformin, are often used to increase effectiveness. For example, combinations of rosiglitazone and metformin (Avandamet) and glyburide and metformin (Glucophage) are proving to be very effective. Metformin may be particularly helpful for patients with unhealthy cholesterol levels and poor control of their blood sugar levels. Some experts recommend a metformin combination as first-line treatment.

Injectable Anti-Hyperglycemic Drugs . In 2005, the FDA approved two new injectable drugs to help patients improve blood sugar control:

• Exenatide (Byetta). Exenatide is the first drug in a new class of drugs called incretin mimetics. It lowers blood glucose levels by increasing insulin secretion. Exenatide is used in combination with oral antihyperglycemics such as metformin or a sulfonylurea drug.
• Pramlintide (Symlin). Pramlintide is a first-in-class drug that is a synthetic form of the hormone amylin. The drug is meant for patients who take insulin but still have difficulty controlling their glucose levels.

Insulin Replacement. Insulin replacement may be required when natural insulin reserves are depleted. It is typically started in combination with an oral drug. Eventually, some patients may need to go on full insulin replacement. In addition to injectable forms of insulin, an inhaled insulin product (Exubera) is now available.

Biguanides (Metformin)

Metformin (Glucophage) is a biguanide, which works by reducing glucose production in the liver and by making tissues more sensitive to insulin. It is now considered by many experts to be the first choice for most type 2 patients who are insulin resistant, particularly if they are overweight. Metformin achieves lower mortality rates from diabetes and all causes than other drugs. In one comparison study, it achieved the lowest mortality rates (8%) compared to insulin (28%), a sulfonylurea (16%), and a thiazolidinedione (14%). Combinations with insulin-secreting drugs, other insulin-sensitizing drugs, or insulin itself are particularly effective.

Metformin does not cause hypoglycemia or add weight, so it is particularly well-suited for obese patients with type 2 diabetes. (In some studies, in fact, patients lost weight.) Metformin also appears to have beneficial effects on cholesterol and lipid levels and may help protect the heart. Some research has suggested that it significantly reduces the risk for heart attack. It is also the first choice for children who need oral drugs and is proving to be very effective for women with polycystic ovary syndrome and insulin resistance.

Side Effects. Side effects include:

• A metallic taste
• Gastrointestinal problems, including nausea, and diarrhea
• Interference with absorption of vitamin B12 and folic acid, (which are important for protection against heart disease)
• Rare reports of lactic acidosis, a potentially life-threatening condition, particularly in people with risk factors for it. Major studies, however, found no greater risk with metformin than with any of the other drugs used for type 2 diabetes.

Certain people should not use this drug, including anyone with heart failure or kidney or liver disease. It is rarely suitable for adults over age 80.

Sulfonylureas

Sulfonylureas are oral drugs that stimulate the pancreas to release insulin. They are also first-line oral drugs. For adequate control of blood glucose levels, the drugs should only be taken 20 - 30 minutes before a meal. A number of brands are available, including chlorpropamide (Diabinese), tolazamide (Tolinase), acetohexamide (Dymelor), glipizide (Glucotrol), tolbutamide (Orinase), and glimepiride (Amaryl).

Most patients can take sulfonylureas for 7 to 10 years before they lose effectiveness. Combinations with small amounts of insulin or with other oral anti-hyperglycemic drugs (such as metformin or a thiazolidinedione) may extend their benefits. In fact, a combination of glyburide and metformin in one pill (Glucovance) is now available. Glucovance may be particularly beneficial for patients with unhealthy cholesterol levels and poor control of their blood sugar levels. Some doctors recommend the combination as first-line treatment.

An encouraging 2000 study of patients with severe type 2 diabetes reporting that combinations of insulin with either chlorpropamide or glipizide (two different sulfonylureas) achieved better glucose control over the long term than insulin alone.

Side Effects and Complications. In general, sulfonylureas should not be used by women who are pregnant or nursing or by individuals who are allergic to sulfa drugs. Side effects may include:

• Weight gain (some sulfonylureas, such as glimepiride, may produce less weight gain than others)
• Water retention
• Although sulfonylureas pose a lower risk for hypoglycemia than insulin does, the hypoglycemia produced by sulfonylureas may be prolonged and dangerous. The newer sulfonylureas, such as glimipiride, have much less risk of hypoglycemia than older sulfonylureas.
• Some sulfonylureas may pose a slight risk for cardiac events.

Sulfonylureas interact with many other drugs, and patients should be sure to inform their doctor of any medications they are taking, including alternative or over-the-counter drugs.

Meglitinides

Meglitinides stimulate beta cells to produce insulin. They include repaglinide (Prandin), nateglinide (Starlix), and mitiglinide. These drugs are rapidly metabolized and short-acting. If taken before every meal, they actually mimic the normal effects of insulin after eating. Patients, then, can vary their meal times with this drug. (Nateglinide appears to work more quickly and is shorter-acting than repaglinide). These drugs may be particularly helpful in combination with metformin or other drugs. They may also be a good choice for people with potential kidney problems.

Side Effects. Side effects include diarrhea and headache. As with the sulfonylureas, repaglinide poses a slightly increased risk for cardiac events. (Newer drugs, such as nateglinide, may pose less of a risk.) People with heart failure or liver disease should use them with caution and be monitored.

Thiazolidinedione

Thiazolidinediones include rosiglitazone (Avandia) and pioglitazone (Actos). They improve insulin sensitivity by activating certain genes involved in fat synthesis and carbohydrate metabolism. These drugs are usually taken once or twice per day; however, it may take several days before the patient notices any results from them and several weeks before they take full effect. Thiazolidinediones are usually taken in combination with other oral drugs or insulin.

In some studies, thiazolidinediones have produced favorable effects on the heart, including reducing blood pressure and preventing blood clots. A 2006 study found that pioglitazone reduced the risk of heart attack, stroke, and acute coronary syndrome. Research presented at the 2005 American Heart Association meeting indicated that pioglitazone may be especially helpful in preventing a second heart attack for patients with type 2 diabetes who have suffered a previous heart attack. Evidence suggests that pioglitazone is superior to rosiglitazone in improving triglyceride and HDL levels. In addition, some evidence suggests that these drugs may preserve beta-cell function and, if used early, may help prevent progression of diabetes. This effect has not been observed with other oral drugs.

Side Effects. Thiazolidinediones can have serious side effects. They tend to increase fluid-build up, which can cause or worsen heart failure in some patients. Combinations with insulin increase the risk. They should not be used by patients with existing heart failure and should be used cautiously in those with risk factors for heart failure. They may cause more weight gain than other antidiabetic medications or insulin. Any patient who experiences sudden weight gain, water retention, or shortness of breath should immediately call their doctors.

There have been rare reports of rosiglitazone causing or worsening diabetic macular edema. This is an eye condition associated with diabetic retinopathy that causes swelling in the macular area of the retina. Symptoms include blurred vision and decreased color sensitivity. Most patients who had this side effect also had swelling in the feet and legs (peripheral edema). The condition resolved or improved when patients stopped taking the drug.

Thiazolidinediones can also cause liver damage. Patients who take these drugs should have their liver enzymes checked regularly.

Alpha-Glucosidase Inhibitors

Alpha-glucosidase inhibitors, including acarbose (Precose, Glucobay) and miglitol (Glyset) reduce glucose levels by interfering with the absorption of starch in the small intestine. Acarbose tends to lower insulin levels after meals, a particular advantage, since higher levels of insulin after meals are associated with an increased risk for heart disease. Some evidence suggests that early use of these drugs may reduce heart risk factors, including high blood pressure. A 2002 study of acarbose suggested that these drugs may even delay the development of type 2 diabetes in high-risk individuals. Alpha-glucosidase inhibitors are not as effective alone as other single oral drugs, but combinations, such as with metformin, insulin, or a sulfonylurea, increase their effectiveness.

Side Effects. These medications need to be taken with meals. Unfortunately, about a third of patients stop taking the drug because of flatulence and diarrhea, particularly after high-carbohydrate meals. The drug may also interfere with iron absorption.

Alpha-glucosidase inhibitors do not cause hypoglycemia when used alone, but combinations with other drugs do. In such cases, it is important that the patient receive a solution that contains glucose or lactose, not table sugar. This is because acarbose inhibits the breakdown of complex sugar and starches, which includes table sugar.

Incretin Mimetics (Exenatide)

Incretin mimetics belong to a new class of drugs that help improve blood sugar control. In 2005, the FDA approved exenatide (Byetta), the first of these drugs. Exenatide is an injectable drug that is a synthetic version of the hormone found in the saliva of the Gila monster, a venomous desert lizard. Exenatide is injected twice a day, 1 hour before morning and evening meals. It is prescribed for patients with type 2 diabetes who have not been able to control their glucose with metformin or a sulfonylurea drug. It can be taken in combination with these drugs or alone.

Side Effects . Exenatide stimulates insulin secretion only when blood sugar levels are high and so has less risk for causing low blood sugar (hypoglycemia) when it is taken alone. However, the risk for hypoglycemia increases when exenatide is taken along with a sulfonylurea drug. There does not appear to be a risk for hypoglycemia when exenatide is used along with metformin. Other side effects may include nausea, vomiting, and diarrhea.

A 2005 study compared exenatide to insulin for improving glucose control in patients taking metformin and a sulfonylurea. Both insulin and exenatide worked well for glucose control. Patients lost weight with exenatide and gained weight with insulin. However, patients who received exenatide had significantly more problems with nausea, vomiting, and diarrhea than those who received insulin.

Insulin Replacement

Insulin replacement is the best treatment for strict control of blood glucose and is required once natural insulin reserves are depleted. Because type 2 diabetes is progressive, most patients eventually require insulin, typically starting it in combination with an oral anti-hyperglycemic drug. However, when a single oral drug fails to control blood sugar it is not clear whether it is better to add insulin replacement or to add a second or third oral drug.

Some experts advocate using insulin as early as possible for optimal control. However, in patients who still have insulin reserves, there is concern that extra natural insulin will have adverse effects. Low blood sugar (hypoglycemia) and weight gain are the main side effects of insulin therapy. Some research suggests that insulin may also cause heart complications. A 2006 study reported that insulin therapy increases the risk of developing high blood pressure (hypertension). It is still not clear if insulin replacement improves survival rates compared to oral drugs, notably metformin.

One approach is to combine insulin with metformin, which achieves blood glucose control without added weight gain. Newer forms of insulin analogues, such as glargine, may be especially helpful for people with type 2 diabetes and reduce the risk for hypoglycemia.

Fortunately, studies to date have not reported any adverse cardiac effects in patients with type 2 diabetes who take insulin. In fact, insulin has been associated, in some cases, with improvement in heart risk factors. More research is needed to clarify these important issues.

Forms of Insulin. Experts are working toward administering insulin so that it closely mimics the daily pattern of insulin, which responds to blood sugar levels by surging after meals and then falling to a steady base level afterward. To achieve this, doctors may use two insulin types:

• Fast-Acting Insulins for Surges. Insulin lispro and aspart are fast-acting insulins. They mimic insulin's response to food intake. They are taken before meals, and their short action reduces the risk for hypoglycemia afterward.
• Slower Insulins for Base Levels. Intermediate forms (including NPH and lente) and long-acting forms (glargine, ultralente) were developed to provide a steady level of insulin throughout the day. To date, glargine (Lantus) seems to be the most successful in achieving this goal in type 2 diabetes.

In 2006, the FDA approved the first non-injected form of insulin. Exubera is an inhaled form of insulin. It is approved for adults but should not be used by patients who smoke or have quit smoking within the past 6 months. Patients with asthma, bronchitis, or emphysema should also not use inhaled insulin. Clinical trials indicate that Exubera can provide sustained blood sugar control over a 2-year period. Patients in the trials who took Exubera experienced half as much weight gain as those who took injected insulin. Scientists are also developing other types of non-injected insulin, including spray formulas.

In a 2005 trial, Exubera improved blood sugar control when it was added to or substituted for combination oral drug therapy (sulphonylurea and thiazolidenedione). However, as with other forms of insulin, Exubera caused more hypoglycemia and weight gain than the oral anti-hyperglycemic drugs.

Pramlintide (Symlin) is a new type of injectable drug that may help patients who take insulin but still need better blood sugar control. The FDA approved this drug in 2005. Pramlintide is a synthetic form of amylin, a hormone that is related to insulin. Pramlintide is used in combination with insulin to lower blood sugar levels in the 3 hours after meals.

[For more detailed information on insulin therapy, see In-Depth Report #9: Diabetes - type 1.]

Investigational Drugs

Gliptins . Gliptins are a new class of drug that is showing promise for improving blood sugar control. These drugs raise the levels of glucagons-like-peptide-1 (GLP-1), a hormone that helps the pancreas produce more insulin but prevents the liver from producing sugar. Scientists hope that gliptins may eventually replace sulfonylurea drugs. Several types of gliptins are currently in late-stage clinical trials. Vildagliptin (Galvus) and sitagliptin (Januvia) are classified as dipeptidyl peptidase-4 (DPP-4) inhibitors. Liraglutide is a GLP-1 analog. Researchers are investigating these drugs in combination with metformin or thiazolidinediones.

• Review Date: 7/15/2006
• Reviewed By: Harvey Simon, M.D., Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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