TABLE Noninsulin Agents for Treatment of Type 2 Diabetes

TABLE Mechanisms to Lower Blood Glucose by Each Antidiabetic Agent

Note: X, main mechanism; (X) less-clear mechanism.

Sulfonylurea

Sulfonylurea preparations have a long record of safety and effectiveness. They work by stimulating insulin secretion by the pancreatic /3-cell, binding to an adenosine triphosphate-sensitive potassium channel, which results in its depolarization, a subsequent influx of intracellular calcium, and the release of insulin. Sulfonylureas are effective both as monotherapy and in combination with other agents that have different mechanisms of action. A significant percentage of patients (up to 10% per year) who are initially properly managed with sulfonylurea monotherapy lose glycemic control over time. Their main side effects include hypoglycemia and weight gain. Hypoglycemia is a serious adverse effect in the elderly and can trigger serious events such as myocardial infarction and stroke. These drugs must be used cautiously in patients with significant renal and hepatic insufficiency, since the liver is the primary site of metabolism and they are excreted by the kidneys. In these settings, the preferred option may be glipizide, whose metabolites are inactive, or glimepiride, which is substantially excreted through the bile.

A commonly used sulfonylurea in younger populations, glyburide, may have age-related impaired absorption and elimination, and elderly subjects appear to have enhanced insulin responses to the drug as well. This may explain, in part, the age-related exponential increase in the frequency of severe or fatal hypoglycemia with this drug.

TABLE Limiting Factors in the Use of Antidiabetic Agents in the Elderly

May impede ischemic preconditioning Frequent dosing may affect compliance; no long-term experience Risk of lactic acidosis; diarrhea Edema; expensive; no long-term experience Frequent dosing may affect compliance; intestinal gas; expensive Injection; expensive; no long-term experience

Note: X, main side effect; XX, pronounced side effect. Abbreviation: wt, weight.

In addition to the type of sulfonylurea, other potential risk factors for hypoglycemia with these drugs in elderly persons include black race, multiple medications, male sex, renal dysfunction, and ethanol consumption. Sulfonylureas should be considered as first-line therapy in lean elderly patients with diabetes. The result in hemoglobin Ale (HbAlc) lowering is approximately 1% to 2% as monotherapy.

Meglitinides

Meglitinides (repaglinide and nateglinide) are nonsulfonylurea drugs that have a distinct β-cell binding profile and stimulate insulin secretion from the β-cell by a mechanism similar to that of sulfonylureas. The potential advantage of this type of drug is that it has a rapid onset and very short duration of action. Meglitinides have been associated with lower frequency of hypoglycemic events when compared with conventional sulfonylureas, presumably because of their shorter duration of action and the fact that the kinetics are not altered with age. Repaglinide lowers HbAlc by 1% to 2%, a reduction similar to that of the sulfonylureas, whereas the glucose-lowering effect of nateglinide is somewhat less potent. Similar changes in fasting glucose and HbAlc values are seen in middle-aged and elderly subjects, suggesting that there is similar efficacy in each age group. Both repaglinide and nateglinide are extensively metabolized by the liver; therefore, they should be used cautiously in patients with hepatic dysfunction. Meglitinides may be considered as an appropriate strategy for elderly patients who have irregular eating habits or have frequent hypoglycemic events on conventional sulfonylureas. These potential benefits must be balanced against the cost of these newer drugs and the compliance problems that could result from a three-times-a-day dosing schedule, particularly in patients who have impaired memory or take may other drugs.

α-Glucosidase Inhibitors

α-glucosidase inhibitors (miglitol and acarbose) impair the breakdown and limit the absorption of carbohydrates from the gut; therefore their major effect is reduction in postprandial glucose excursions. These drugs are associated with less weight gain and a lower frequency of hypoglycemia than sulfonylureas. The residual carbohydrates in the intestinal lumen cause diarrhea in about 25% of patients taking these drugs. Gradual dose titration is crucial to minimize gastrointestinal side effects and achieve better compliance. Their overall effect on HbAlc concentration is a modest reduction of 0.5% to 1%. In a recent randomized multicenter trial of the a-glucosidase inhibitor acarbose in obese elderly patients with diabetes, acarbose reduced HbAlc by about 0.8% when compared with placebo and also resulted in an improvement in insulin sensitivity. α-glucosidase inhibitors are useful drugs as primary therapy for elderly patients with modest fasting hyperglycemia, especially if they are obese. They can also be used in patients taking other oral agents to enhance glycemic control. Hypoglycemia may occur if these agents are used in combination with sulfonylureas or insulin; consequently, only glucose should be used for prompt treatment of hypoglycemia because the absorption of other carbohydrates is delayed. Acarbose has minimal systemic absorption, yet some hepatic metabolism occurs and because of rare but possible hepatotoxicity, it is contraindicated in patients with advanced liver disease. In contrast, as much as 50% to 90% of the miglitol dose may be absorbed but is not metabolized in the liver but rather eliminated through the kidney. Therefore, miglitol should not be used in patients with renal failure.

Metformin

Metformin is currently the only biguanide available in North America. Its mechanism of action is to improve insulin sensitivity, chiefly by reducing insulin resistance in the liver, thereby decreasing hepatic glucose production. In addition, its glucose-lowering effect is accompanied by a reduction in plasma insulin concentration, and some experts refer to metformin as an insulin sensitizer. Metformin lowers HbAlc by 1% to 2%. Although, the most important side effect associated with biguanides is lactic acidosis, this is rare with metformin; and aging itself does not appear to be a risk factor provided that careful attention is paid to the contraindications for this drug (significant liver, renal, and cardiac disease). Clinical studies suggest that the drug is safe and effective as monotherapy in obese older people. In our view, metformin is an ideal drug for first-line therapy of obese older patients, because it increases insulin sensitivity, assists with weight loss, reduces lipid levels, and does not cause hypoglycemia. The recently published ADA management algorithm suggests the use of metformin, together with lifestyle intervention, as initial monotherapy.

In addition, metformin is a useful adjunct for patients who are inadequately controlled on maximum doses of sulfonylureas. Metformin is contraindicated in older subjects with renal insufficiency, in men with a serum creatinine level of 1.5 mg/dL or higher or women with a serum creatinine level of 1.4 mg/dL or higher. Serum creatinine should be measured at least annually and with any increase in dose of metformin. It should be noted, however, that serum creatinine does not adequately reflect the renal function in the elderly. For those aged 80 years or older or those suspected to have reduced muscle mass, a timed urine collection for creatinine clearance should be obtained. Metformin should be avoided if the value is less than 60 mL/ min. Metformin should be temporarily discontinued during radiographic studies that use iodinated contrast agents, during acute illness, and during most hospitalizations. Clinical situations where tissue perfusion is compromised (sepsis, dehydration, pulmonary disease with hypoxemia, and acute or advanced heart failure) also contraindicate the use of metformin.

Thiazolidinediones

Thiazolidinediones (rosiglitazone and pioglitazone) improve insulin sensitivity primarily in muscles and adipocytes, thereby increasing peripheral uptake and utilization of glucose. They are generally well tolerated and appear to be as effective in older patients as in younger patients, with an approximate 1.5% reduction in HbAlc and with a dose-dependent glucose-lowering effect, which may take four to eight weeks. In addition to benefits of these drugs on cardiovascular and metabolic markers, a recent randomized trial has shown the effect of pioglitazone on the reduction of cardiovascular outcomes in patients with type 2 diabetes. Thiazolidinediones do not lead to hypoglycemia unless they are used in conjunction with secretagogues or insulin. Hepatic toxicity has not been reported in elderly subjects, but liver function tests should be monitored regularly. The incidence of edema and anemia is higher in elderly patients than in middle-aged patients treated, and volume status and blood count need to be carefully monitored. Thiazolidinediones-related fluid retention is a major contributor to increased body weight, typically manifests as peripheral edema, and develops predominantly within the first months of treatment. Thiazolidinediones can be a useful first-line therapy in obese elderly patients, particularly for those patients who cannot tolerate metformin or those who have a contraindication to it. In fact, thiazolidinediones can be safely used in patients with renal impairment provided that the cardiac function is preserved. In addition, they may be a beneficial adjunct therapy in elderly patients who have suboptimal glycemic control, despite insulin requirements of 50 or more units per day.

Controlling your blood sugar levels can be an ongoing challenge. Many different factors affect your blood sugar levels, including diet, activity, stress, and overall health. Knowing how much to eat, how much to exercise, and how much medication and/or insulin to take can be difficult. Keep in mind that your type 2 diabetes care team is available for support.

Making Blood Sugar Control More Manageable

When you have type 2 diabetes, it is easy to get caught up in the day-to-day actions that are required to manage your condition. Sometimes all of the “shoulds” and “should nots” can feel overwhelming. To make your daily efforts more manageable, it may be helpful to think about all your reasons for controlling your blood sugar. You may want to consider posting a list of these reasons where you will see it often.

There are other approaches you can take that might make the steps along the way easier. Try Glucophage XR. For example, if you plan to increase your physical activity, start by taking a 15-minute walk 3 times a week. Then try walking longer or more often. Remember, a big part of the process is learning what works for you. Your healthcare team can help you construct a manageable diabetes care plan.

In addition to exercise, diet, and weight loss, some people with type 2 diabetes need medication to keep their blood sugar levels under control. If you require medication to help control your blood sugar, you may want to ask your doctor or healthcare professional if Glucophage XR may be right for you.

* Extreme thirst

* Frequent urination

* Extreme hunger

* Unexplained weight loss

* Unexplained fatigue

* Blurry vision

* Tingling or numbness in the hands, feet, or legs

* Itchy skin

* Frequent infections of the skin, gums, vagina, or bladder

* Slow healing of cuts and scrapes

If you learn that you have type 2 diabetes and diet and exercise are not enough, treatments are available that may help you control your blood sugar levels. One such treatment is Glucophage XR. Ask your doctor or healthcare professional if Glucophage XR may be right for you.

Drug trade names: Glucophage XR, Riomet, Fortamet, Glumetza, Obimet, Dianben, Diabex, Diaformin

Metformin is the only biguanide currently approved for the treatment of type 2 diabetes mellitus. It was originally developed in the 1950s in Europe and has been used there for many years. This agent was approved for use in the United States in 1995. While the mechanism of action is not completely clear at the present time, we do know that metformin is not an insulin secretagogue. It is effective in reducing hepatic and renal gluconeogenesis, thereby lowering fasting blood glucose values. Metformin also is effective in reducing postprandial blood glucose by a mechanism that is thought to involve retardation of gastrointestinal absorption. There also are some data that metformin improves peripheral insulin sensitivity by increasing the expression of glucose transporters and by increasing non-oxidative glucose metabolism.

Metformin usually is given initially as one 500-mg tablet once daily with a meal. One week later, the dose should be increased to 500 mg twice daily and can eventually reach a maximum of 2500 mg/day. Most studies show maximum effect with 2000 mg/day, with no additional efficacy at 2500 mg/day. There also are 850-mg tablets, allowing for convenient twice-daily dosing. Most studies analyzing the effects of metformin show that patients will on average lower HgbA₁C by 1.5%-1.9% when it is used as monotherapy.

This agent can be added to a sulfonylurea or insulin therapy (Current Oral Antidiabetic Therapy: A Summary of Oral Therapy), in which case a further decrease in HgbA₁C of 1.5% can be expected. Metformin alone is not associated with hypoglycemia, but this can occur when combined with insulin or sulfonylurea therapy. Metformin has the added benefit of reducing triglycerides and inducing mild weight loss in some overweight patients. The use of metformin to achieve glycemic control was studied in a subset of 342 obese diabetic patients in the United Kingdom Prospective Diabetes Study (UKPDS). Although reduction in myocardial infarction endpoints did not quite reach statistical significance (P<.052) in the insulin- and sulfonylurea-intensively treated groups, the obese diabetic patients treated with metformin had significant reductions in myocardial infarction, nonfatal stroke, and all cause mortality. The increased effect of metformin on prevention of macro vascular disease may be related to its known effects on decreasing low-density lipoprotein and triglyceride levels. More information should be available with the release of the UKPDS results concerning lipid profiles.

The main potential complication of metformin use is the risk of lactic acidosis. Unlike its predecessor phenformin, metformin does not strongly inhibit oxidative metabolism of glucose. Due to the absence of this effect, the risk of lactic acidosis is present, but much lower. The incidence of lactic acidosis is quite rare; however, it is recommended to avoid using metformin in patients who are predisposed to lactic acidosis or cannot metabolize lactate. Therefore, patients with a history of hepatic insufficiency, renal insufficiency, severe cardiac or respiratory disease, chronic metabolic acidosis, or alcohol abuse should not take metformin. It also is recommended that metformin should be stopped at the time of any interventional procedures, particularly surgical procedures or those requiring contrast dye. This will prevent a rise in metformin levels should acute renal failure occur. Metformin also should be used with caution in elderly patients secondary to their diminished renal function.

There are no known drug interactions and the most commonly seen side effect from metformin use is gastrointestinal irritation. Administering the tablet with food and beginning with the 500-mg dose usually prevents or ameliorates this side effect. Less than 5% of individuals will actually require cessation of metformin due to gastrointestinal side effects.

Switching from Glucophage to Glucophage XR can help to make your daily routine less complicated and make it easier for you to stick with your medication. Plus, clinical studies have shown that the blood sugar lowering effect of Glucophage XR, taken once daily, is comparable to the original Glucophage.

Glucophage XR is an extended-release formulation of Glucophage; this means that unlike Glucophage, Glucophage XR is designed to be taken once daily. By switching from Glucophage to Glucophage XR, you may cut down on the number of times a day that you must take this type 2 diabetes medication.

If you are looking for an effective and convenient way to help lower your blood sugar levels, ask your doctor about switching to Glucophage XR today!

Ask Your Doctor

Why should you talk to your doctor or healthcare provider about new Glucophage XR?

* Glucophage XR is a once-daily dose of Glucophage® (metformin hydrochloride tablets). When diet and exercise are not enough, and medication is needed, Glucophage XR offers most type 2 diabetes patients convenient and effective blood sugar control.

* Glucophage XR’s extended-release formula is designed for convenient once-a-day dosing. This makes it easier to take your medication as prescribed, which helps to ensure that you achieve and maintain blood sugar control.

* Glucophage XR is from the makers of Glucophage, the number one prescribed diabetes pill.

Benefits

* Because Glucophage XR is an extended-release medication, it usually can be taken only once per day.

* In clinical trials, Glucophage XR was shown to be comparable to Glucophage in improving control of blood sugar levels.

* Glucophage XR offers the benefit of being a convenient and effective way to help lower blood sugar levels.

Taking control of type 2 diabetes includes regular exercise, weight control, and eating healthy foods. Another important step is taking your medication as prescribed. When it comes to medication, if you’re looking for effective and convenient blood sugar control, Glucophage XR may be the answer for you.

Taking Glucophage XR

* Follow your doctor’s instructions about how much medicine to take and when to take it. (Your doctor may slowly increase your dose until your blood sugar levels are better controlled.)

* You should take Glucophage XR with meals (typically the evening meal when dosed once-daily).

* Your doctor may prescribe other medication along with Glucophage XR to help you achieve the best control of your blood sugar levels. Follow your doctor’s instructions about any of these other medications.

* Continue your diet and exercise program and test your blood sugar regularly.

Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally. There is no evidence that Glucophage XR causes harm to the liver or kidneys, but it is important to make sure that they are working properly.

This section provides information on commonly used tests to diagnose type 2 diabetes. Only your doctor or healthcare professional can determine if you have type 2 diabetes.

Fasting Glucose Test

Diabetes is most often diagnosed using a fasting glucose test. For this test, you will be asked to go without eating for 10 to 16 hours, usually overnight, before a blood sample is drawn. The test will measure the amount of glucose in your blood. If your glucose level is equal to or greater than 126 milligrams per deciliter (mg/dL) on two or more fasting glucose tests performed on different days, you have type 2 diabetes.

This chart shows how the fasting glucose test is interpreted.

Oral Glucose Tolerance Test

In some instances, an oral glucose tolerance test may be performed to diagnose type 2 diabetes. When taking this test, you will usually be asked to eat a diet that is high in carbohydrates for 3 days. Before the test, you will have to fast for 10 to 16 hours, usually overnight. When you go to the office or laboratory, you will first have a fasting blood sample drawn. You will then be asked to drink a sweet liquid that contains glucose. Samples of your blood will be taken 5 times over a period of 3 hours. Your doctor or healthcare professional will give you specific instructions prior to having a glucose tolerance test.

In a person who does not have type 2 diabetes, the glucose (sugar) levels in the blood will rise and then fall quickly. In someone with type 2 diabetes, blood glucose levels will often rise higher than normal and will not drop as fast. If your blood sugar level is above 200 mg/dL at 2 hours, you may have diabetes. Your doctor or healthcare professional will either repeat the test or perform a fasting glucose test on a different day to confirm the diagnosis.

After an oral glucose tolerance test, if the blood glucose levels are somewhere between those of a person without type 2 diabetes and a person with type 2 diabetes, a person is said to have impaired glucose tolerance. Although people with this condition may not have type 2 diabetes, they are at increased risk of developing it. If you have impaired glucose tolerance, your doctor or healthcare professional may recommend that you lose weight and exercise to help manage your risk of developing type 2 diabetes.

This chart shows how the oral glucose tolerance test is interpreted.

Random Glucose Test

When symptoms of diabetes are present, a blood sample that is taken in a non-fasting state (otherwise known as a random blood sample) may be used to test for type 2 diabetes. In this case, a glucose (sugar) level of greater than 200 mg/dL accompanied by symptoms of hyperglycemia suggests a person may have type 2 diabetes. However, the result must be confirmed on another day by performing a fasting glucose test or an oral glucose tolerance test.

If you have been diagnosed with type 2 diabetes and diet and exercise no longer control your blood sugar, treatments are available that may help you lower your blood sugar levels. One such treatment is Glucophage XR. Ask your doctor or healthcare professional if Glucophage XR is right for you.

* Have a family member who has type 2 diabetes

* Are overweight

* Are over 65 years of age

* Are of African-American, Hispanic/Latino, American-Indian, Asian-American, or Pacific-Islander descent

* Have high blood pressure

* Have very high cholesterol or triglyceride levels

* Are not very physically active (get less than 30 minutes of exercise 3 days a week)

* Are a woman who developed type 2 diabetes while pregnant (a condition called gestational diabetes)

* Are a woman who has experienced an unexplained miscarriage or stillbirth or had babies weighing 9 pounds or more at birth

Take advantage of our interactive type 2 diabetes risk assessment tool.

If you are at risk for developing type 2 diabetes, there are several things you can do that may manage your risk, such as exercising regularly, eating healthy foods, and watching your weight. Your doctor or healthcare professional can work with you to develop a program that’s right for you.

If you have been diagnosed with type 2 diabetes and your doctor or healthcare professional has recommended that you control your blood sugar levels with medication in addition to eating healthy foods and exercising regularly, ask him or her if Glucophage XR is right for you.

Some people may be more likely to develop type 2 diabetes because they have various risk factors, such as their genetic make-up, body type, and activity level.

People who carry a genetic trait for type 2 diabetes and who are overweight may develop type 2 diabetes more rapidly. In these people, extra body fat may cause cells to become resistant to the effects of insulin (called insulin resistance). When this happens, the pancreas attempts to compensate by producing more insulin. Eventually, the pancreas may not be able to keep up with the body’s demand for increased levels of insulin, causing an abnormal increase in blood sugar levels. This condition is called impaired glucose tolerance, which can potentially lead to type 2 diabetes, hypertension, and heart disease.

Fortunately, there are steps you can take that may help manage your risk of developing type 2 diabetes. Some people are able to avoid type 2 diabetes by making changes to their lifestyle, such as eating less and exercising more regularly. It is also important to look at other type 2 diabetes risk factors that you may have. Ask your doctor or healthcare professional how to manage your risk factors.

If you have been diagnosed with type 2 diabetes and diet and exercise cannot adequately control your blood sugar, effective medication is available. Glucophage XR is a convenient and effective way to help lower high blood sugar levels. See your doctor or healthcare professional to find out if treatment with Glucophage XR may be right for you.

At the time, Glucophage was a unique discovery and an important advancement for lowering blood sugar in the treatment of type 2 diabetes, because it did not make the body produce more insulin. Instead, it helped the body to respond better to its own insulin, to decrease glucose production by the liver, and to decrease sugar absorption from the intestine. Ultimately, this product, in conjunction with diet and exercise, helped to control a patient’s blood sugar level.

The Development of a New Type 2 Diabetes Medication

French pharmacist Jan Aron introduced Glucophage in 1958, and along with Dr. Jean Sterne, assembled and led a team that developed this important type 2 diabetes medication. Their persistence and faith brought “new hope” to people with type 2 diabetes.

Confident that he developed a product that could help lower blood sugar in patients with type 2 diabetes, Aron planned the launch of Glucophage in France at the end of 1958.

Glucophage is Introduced to the World

On December 11, 1958, Glucophage was granted approval by the French Ministry of Health. At the time, the idea of launching a type 2 diabetes product that did not cause the body to make more insulin was a gamble. However, through word-of-mouth among the French medical community, Glucophage began to build a reputation of being a product that could help lower blood sugar in patients with type 2 diabetes.

Beginning in February 1960, Aron began sending out sales representatives throughout France to inform doctors about Glucophage. Once the drug was prescribed and used by patients, the representatives returned to discuss the results. The results affirmed that Glucophage is a safe and effective treatment for type 2 diabetes. Therefore, the product’s favorable reputation spread rapidly.

Combined Therapy With Sulfonylurea is Confirmed

Two years after the launch of Glucophage, Aron Laboratories confirmed a new finding about the product. Dr. Jean Sterne observed that in patients whose blood sugar was not controlled with Glucophage alone, a combination of Glucophage with a sulfonylurea agent made it possible for some patients to lower their blood sugar levels.

Today, Glucophage is still often used in combination with a sulfonylurea.

The 850 mg Glucophage Tablet is Introduced

In 1969, introduction of an 850 mg tablet made it more convenient to administer higher doses of Glucophage, when needed.

Glucophage is Introduced in America

By the mid-1980s, Glucophage was sold in countries all over the world, except in the United States of America.

A company named LIPHA became responsible for Glucophage in the 1980s, and began the process of obtaining approval in the U.S. for the product.

LIPHA also began a search for an American partner to market Glucophage. Since type 2 diabetes is generally treated in family practice in the United States, LIPHA looked for a partner with a network of representatives all across the country. The choice was Bristol-Myers Squibb. In March 1995, after 8 years of clinical trials and registration procedures, Glucophage was cleared for marketing in the United States.

Although he did not live to see it, Jan Aron’s dream was finally realized. His “little product” had become the most prescribed diabetes pill in the United States.

The Development of a Once-Daily Dose — Glucophage XR

In October 2000, the U.S. Food and Drug Administration (FDA) approved Glucophage XR, a once-daily dosing formulation of the original Glucophage. View the press release announcing the approval.

Glucophage XR is a registered trademark of LIPHA s.a. Glucophage is a registered trademark of LIPHA s.a. Licensed to Bristol-Myers Squibb Company.