Diabetes: Type 2

Description

Alternative Names

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. Although to date tight control of blood glucose has not proven to reduce mortality rates from all causes or cardiovascular diseases in patients with type 2 diabetes, evidence is increasing that intensive control has benefits for the heart as well--although they may not be evident as rapidly.

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

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

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

• Biguanides (metformin). Increase 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 type 2 patients who are insulin resistant.
• Sulfonylureas (examples include glyburide, glipizide, and glimepiride). Stimulate insulin secretion.
• Meglitinides (repaglinide, nateglinide). Stimulate insulin secretion. These newer agents are better than sulfonylureas in controlling glucose spikes after meals.
• Thiazolidinediones (pioglitazone and rosiglitazone). Reduce insulin resistance. These agents 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. The drugs have not been intensively studied, and some experts believe they should not be used except in clinical studies.
• Alpha-glucosidase inhibitors (acarbose and miglitol). Slow intestinal absorption of carbohydrates. Have only modest effects and have gastrointestinal side effects.

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

Adding Insulin Replacement. Insulin replacement is usually required as natural insulin reserves are depleted. It is typically started it combination with an oral agent. Eventually, some people may need to go on full insulin replacement.

Metformin (a Biguanide)

Metformin (Glucophage) is a biguanide, which appears to work by reducing glucose production in the liver and by making tissues more sensitive to insulin. It is now be 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 type 2 patients. (In some studies, in fact, patients lost weight.) Metformin also appears to have beneficial effects on cholesterol and lipid levels and may be heart protective. Some research, in fact, has suggested that it significantly reduces the risk for heart attack. It is also the first choice for children who need oral agents and is proving to be very effective for women with polycystic ovaries and insulin resistance.

Side Effects. Side effects include the following:

• A metallic taste.
• Gastrointestinal problems, including nausea, and diarrhea.
• It may also reduce absorption of vitamin B12 and folic acid, which are important for protection against heart disease.
• There have been some 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 congestive heart failure or kidney or liver disease. It is rarely suitable for adults over 80.

Sulfonylureas

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

Most patients can take sulfonylureas for seven to 10 years before they lose effectiveness. Combinations with small amounts of insulin or with other 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 experts recommend the combination as first-line treatment.

Also encouraging was a 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 include the following:

• 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, appear to have about one tenth the risk of hypoglycemia than do older sulfonylureas.
• Some may pose a slight risk for cardiac events.

Sulfonylureas interact with many other drugs, and patients should be sure to inform their physician 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 agents are rapidly metabolized and short acting and 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 agents may be particularly effective in combination with metformin or other agents. And they may be good agents 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 agents, 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 do not cause hypoglycemia when used alone, although they are usually taken in combination with oral agents or insulin.

In some studies, thiazolidinediones have produced favorable effects on the heart, including reducing blood pressure and preventing blood clots. Pioglitazone improves triglyceride and HDL levels. (Rosiglitazone has mixed effects on lipid levels.) Of importance, some evidence suggests that these agents may preserve beta-cell function and, if used early, may help prevent progression of diabetes. This effect has not been observed with other standard oral agents.

Side Effects Nevertheless, 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 at all in patients with existing heart failure and should be used cautiously in those with risk factors for heart failure. Any patient who experiences sudden weight gain, water retention, or shortness of breath should call their physicians immediately.

Thiazolidinediones can cause also anemia and, as with other oral agents, can cause moderate weight gain. There have been a few reports of liver injury. At this time some experts believe thiazolidinediones should not be used routinely for managing type 2 diabetes but only in the context of clinical studies.

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 agents may reduce heart risk factors, including high blood pressure. A 2002 study using acarbose also suggested that these agents might 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 to 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.

Insulin Replacement

Issues Involves with Insulin Replacement. Insulin replacement is the best treatment for strict control of blood glucose and is required as natural insulin reserves are depleted. Because type 2 diabetes is progressive, most patients eventually require insulin, typically starting it in combination with an oral agent. However, when a single oral agent 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 agent. A 2003 study reported that three oral agents were as effective as insulin plus an oral agent, but the costs are significantly higher. Some experts advocate using insulin as early as possible for optimal control.

However, in patients who still have insulin reserves, there is some concern that extra natural insulin will have adverse effects, including hypoglycemia, weight gain, and heart complications. It is still not clear if insulin replacement will improve survival rates compared to oral agents, notably metformin.

One approach that might solve some of these problems 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 specifically 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 are taking 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, physicians may use two insulin types:

• Fast-Acting Insulins for Surges. Insulin lispro and insulin 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 (insulin glargine, ultralente insulin) have been 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.

Noninjected forms of insulin are under investigation and may be particularly beneficial for type 2 diabetes. For example, preprandial inhaled insulin, or INH, is used with an inhaler, and Oralin is administered using an oral spray that is absorbed in the cheek lining. In one study, INH was added to oral agents administration and inhaled before meals. After 12 weeks it was more effective in controlling blood glucose, although patients gained weight and had a great incidence in hypoglycemia.

[For more detailed information on insulin therapy, see Well-Connected Report #9, Diabetes: Type 1.]

Investigative Agents

Incretins. Incretins are hormones that are released from the intestine and enhance insulin secretion. Glucagon-like insulinotropic peptide, or GLP-1 (Betatropin), is an incretin under investigation. It appears to help metabolize glucose and reduce appetite. Betatropin is administered using injections. Early studies report that it is effective in controlling blood glucose levels and has also been associated with weight reduction. A transmucosal tablet (placed between the lip and gum) is also under investigation and is showing benefits.

Pramlintide. Pramlintide (Symlin), known as an amylin analog, is derived from a natural hormone that acts in concert with the body's insulin in the pancreas to control hyperglycemia. It slows stomach emptying and delays absorption of nutrients in the intestine. It therefore prevents the surge in blood sugar that typically occurs after meals. Some studies indicate that in combination with insulin it helps control glucose levels, importantly after meals, without increasing the risk for hypoglycemia or increasing weight when added to insulin regimens. It is being considered for approval for both type 1 and type 2 insulin-dependent diabetes. One possible adverse effect is a delay in stomach emptying, which is already a complication of diabetes in some patients with neuropathy.

D-Chiro-Inositol. D-chiro-inositol (INS-1) is an investigational agent that increases sensitivity to insulin. It is showing promise in treating people with less severe diabetes and women with polycystic ovary syndrome. More research is underway.

Ciliary Neurotrophic Factor. An agent derived from ciliary neurotrophic factor (Axokine) signals the brain to suppress appetite. It is proving to be effective in achieving weight loss, and also improves cholesterol, lipid, and glucose levels regardless of food intake. The agent, then, may be particularly helpful for people with type 2 diabetes. It is currently in late trials.

Exenatide. Exenatide (Heloderma) is derived from the venom of the Gila monster. Animal and laboratory studies suggest that it enhances insulin secretion and slows stomach emptying. It may also have some protective effects on beta cells. Early studies are reporting reductions in HbA1C when used in combination with metformin, sulfonylureas, or both.