Antidiabetic Agents

Antidiabetic Agents

Also called: Antihyperglycemic Agents, Oral Hypoglycemic Agents, Hypoglycemic Agents


Antidiabetic agents are drugs used to treat type 2 diabetes, in addition to exercise and diet. These drugs help lower blood glucose (blood sugar) levels.

Classes of oral diabetes medications include:

  • Alpha-glucosidase inhibitors
  • Biguanides
  • Meglitinides
  • Sulfonylureas
  • Thiazolidinediones
  • A new group called DPP-4 inhibitors

In addition to these pills, the U.S. Food and Drug Administration (FDA) has approved the first in a new class of injected medications for type 2 diabetes called incretin mimetics. And there is an injectable medication called synthetic amylin that is the only drug other than insulin approved to treat type 1 diabetes. Synthetic amylin can also be prescribed to insulin-dependent patients with type 2 diabetes.

Many additional diabetes drugs are under development. Antidiabetic agents do not cure diabetes, but they can help manage it. Other crucial parts of the treatment plan include diet, exercise, glucose monitoring, regular medical care and sometimes insulin.

About antidiabetic agents

Antidiabetic agents are drugs that treat type 2 diabetes by lowering glucose (blood sugar) levels in patients. During physical exercise, the muscles use glucose as energy. When diet and exercise control glucose, the patient does not require medications. In addition to meal planning, physical activity and weight loss, medications may be prescribed if those methods by themselves cannot control a patient’s type 2 diabetes.

Type 2 diabetes is a condition of abnormally elevated blood glucose levels. Typically, this is because muscle and fat cells in the body are resistant to absorbing glucose. As a result, glucose remains trapped in the bloodstream instead of entering the cells and providing the body with energy. Over time in type 2 diabetes the pancreas produces less insulin, the hormone that moves glucose from the blood into the cells. This results in insulin deficiency and is the other major contributing cause of elevated blood glucose (hyperglycemia).

There are two sources of the glucose found in the body: foods consumed by the individual, and sugar produced in the liver converted from stored body fats, proteins and glycogen.

Antidiabetic agents work by either:

  • Limiting the amount of glucose that gets into the bloodstream
  • Encouraging the movement of glucose from the bloodstream to the cells

According to the U.S. Centers for Disease Control and Prevention (CDC), 11.6 million adults with diabetes report taking some type of medication to control their condition. Of these adults, 7.8 million reported taking only oral antidiabetic agents, 2.1 million reported taking only insulin, and 1.7 million reported taking both. These figures are from 2003 and had not been updated as of December 2007. However, the number of people taking antidiabetic agents has likely risen because the incidence of diabetes has been soaring. Between 2002 and 2005 alone, the number of children taking antidiabetic agents doubled.

Managing type 2 diabetes with antidiabetic agents can provide short-term and long-term health benefits. These include:

  • Short-term
    • Feeling healthy and more energetic
    • Preventing symptoms related to high blood glucose (hyperglycemia), such as excessive thirst, blurry vision, excessive weight loss or weight gain.
    • Preventing consequences of poorly controlled glucose, such as diabetic ketoacidosis, hyperosmolar hyperglycemic nonketotic syndrome (HHNS) and diabetic coma
  • Long-term
    • Reducing odds of developing cardiovascular conditions, eye diseases (such as diabetic retinopathy and glaucoma), kidney disease (diabetic nephropathy), nerve damage (diabetic neuropathy), sexual dysfunction, foot conditions, skin problems and gum disease
    • Improving cholesterol and triglyceride levels
  • Diminishing insulin resistance
  • Enhancing long-term quality of life

Diabetes treatments are designed to maintain blood glucose levels within a range that is considered normal and healthy. This is less than 110 milligrams per deciliter (mg/dL) during fasting periods and under 140 mg/dL after meals, according to the American Diabetes Association (ADA). Antidiabetic agents do not work for everyone with type 2 diabetes. Most people will experience a drop in their blood glucose level, but not everyone will experience a decrease to normal, healthy levels.

The effectiveness of oral antidiabetic therapy is lower for those who have had type 2 diabetes for more than 10 years or who take more than 20 units of insulin a day. In some cases, the pills work initially but lose their effectiveness after five to seven years of treatment. Antidiabetic agents are generally not effective in very thin people.

Antidiabetic agents are most effective in treating type 2 diabetes when they are used as part of a comprehensive physician-prescribed management plan. This plan typically provides for an appropriate diet, along with exercise, weight loss, glucose monitoring, regular medical care and a sick-day plan. The benefits of antidiabetic agents may be compromised if patients do not take these other steps to improve their well-being.

In addition to antidiabetic agents, medications are being developed to treat or prevent diabetic complications of the kidneys, nerves and eyes.

Furthermore, people with type 2 diabetes or prediabetes are frequently prescribed medication to treat diabetic conditions and risk factors such as high blood pressure, unhealthy cholesterol levels (hyperlipidemia) and obesity. Diabetic patients may also be prescribed glucagon, a hormonal drug that can be injected in case of severe hypoglycemia or insulin shock.

Some companies market herbal preparations as medications for diabetes. These are not regulated by the U.S. Food and Drug Administration and may contain various quantities of beneficial, ineffective or harmful ingredients. Patients are advised not to use them without approval by their physician.

Types and differences of antidiabetic agents

Until 1994 only one class of oral medications was used to treat type 2 diabetes in the United States. These drugs, known as sulfonylureas, work by enhancing pancreatic production of insulin to reduce glucose (blood sugar) levels. Today, there are a variety of antidiabetic agents available. Oral diabetes drugs sold in the United States belong to six classes, each with their own advantages and disadvantages:

  • Sulfonylureas. Stimulate the beta cells in the pancreas (a gland in the abdomen) to make more insulin. They may cause hypoglycemia (low glucose), weight gain and sensitivity to the sun. Some controversial research has linked these medications to increased risk of cardiovascular problems and death, though some other studies have found they may have cardiovascular benefits. Sulfonylureas include:
    • chlorpropamide (Diabinese)
    • glimepiride (Amaryl)
    • glipizide (Glucotrol)
    • glyburide (Diabeta, Glibenclamide, Glycron, Glynase, Micronase)
    • tolazamide (Tolinase)
    • tolbutamide (Orinase)
    • acetohexamide (Dymelor), which is no longer available in the United States
  • Meglitinides. Like sulfonylureas, these stimulate the beta cells in the pancreas to make more insulin. They may cause hypoglycemia and weight gain. Meglitinides include:
    • nateglinide (Starlix)
    • repaglinide (Prandin)

      Nateglinide has also been classified as the first in a type of antidiabetic agent called D-phenylalanine derivatives, which make the pancreas more sensitive to insulin.
  • Biguanides. Diminish insulin resistance, decrease the amount of glucose produced by the liver and help muscles better absorb glucose in the blood. Unlike some other antidiabetic agents, they do not promote insulin secretion, making them less likely to trigger hypoglycemia. These medications are not recommended for patients with kidney damage or heart failure.

    The only biguanide approved by the U.S. Food and Drug Administration (FDA) is metformin, sold under the brand names Glucophage, Diabex, Diaformin, Fortamet, Glumetza and Riomet (a liquid). A biguanide called buformin might still be available in some other countries.
  • Thiazolidinediones (TZDs). Help make muscle and fat more sensitive to insulin and reduce glucose production in the liver. These pills can significantly reduce the amount of insulin that patients need to take via injections. They may have rare but serious effects on the liver. TZDs include:
    • pioglitazone (Avandia)
    • rosiglitazone (Actos)

      In 2007 the FDA strengthened warning labels on TZDs because of new concerns about their cardiac risks. Also in 2007, the makers of both TZDs announced studies indicating the drugs might increase women’s risk of bone fractures.
  • Alpha-glucosidase inhibitors (AGIs). Prevent or slow the absorption of some carbohydrates in the intestine, which moderates blood glucose levels after meals. Diarrhea, flatulence and abdominal cramping have limited the use of these types of medications. AGIs include:
    • acarbose (Glucobay, Prandase, Precose)
    • miglitol (Glyset)
    • voglibose (Volix, Basen)
  • DPP-4 inhibitors. These agents use a new approach that affects the pancreatic alpha cells and beta cells, resulting in reduced release of glucose from the liver and increased production of insulin. The FDA approved the first DPP-4 (dipeptidyl peptidase-4) inhibitor, sitagliptin (Januvia), in October 2006. The FDA has sought more safety data on a similar drug, vildagliptin (Galvus), which has received approval from European regulators. Other DPP-4 inhibitors under development include saxagliptin and SYR-322. DPP-4 inhibitors may be prescribed alone or in combination with metformin, sulfonylureas or TZDs. They are generally taken once a day.

    The most common side effects of sitagliptin have been upper respiratory infection, sore throat and diarrhea. The most common side effects of vildagliptin have been cold-like symptoms, headache and dizziness. Like other diabetes pills, DPP-4 inhibitors are not used to treat type 1 diabetes or diabetic ketoacidosis.

In addition to these oral medications, the FDA in 2005 approved two injected medications for diabetes:

  • Incretin mimetics. Exenatide (Byetta) is the first in a new class of medications for type 2 diabetes called incretin mimetics. This class of drug is also known as an incretin or GLP agonist. Exenatide stimulates the body to release more insulin and reduce the levels of another hormone called glucagon. Glucagon is a “counter-regulatory” hormone that opposes the effects of insulin. Unlike most diabetes drugs, exenatide has helped many patients lose weight. Other incretins are being developed.

    Exenatide is a synthetic version of exendin-4, a hormone (natural chemical messenger) found in the saliva of the Gila monster. This venomous desert lizard eats only a few times a year. When not eating, it is able to turn off its pancreas, which stops the flow of insulin. When it is time to eat again, the Gila monster secretes exendin-4, which turns on the pancreas.

    Exenatide can be taken in addition to metformin, a sulfonylurea or a TZD. Patients inject it twice a day, before the morning and evening meals, using a 60-dose prefilled pen similar to an insulin pen.

    insulin pen Before taking exenatide, according to the FDA, patients should inform their physician if they have gastroparesis, have severe kidney disease (e.g., diabetic nephropathy), are on dialysis, are pregnant or planning to become pregnant, or are breastfeeding. Possible side effects include decreased appetite, nausea, vomiting, diarrhea, dizziness, headache, jitteriness, acid stomach and, if taken with a sulfonylurea, hypoglycemia.

  • Synthetic amylin. Pramlintide (Symlin) may be prescribed to people with type 1 diabetes or type 2 diabetes who already use insulin but need better control of their glucose. Pramlintide is the first drug other than insulin approved to treat type 1 diabetes. It is a synthetic version of amylin, a hormone made in the beta cells of the pancreas. It is taken at mealtimes and must be injected separately from insulin a different syringe.

    According to the FDA, patients should not use pramlintide if they have gastroparesis or hypoglycemia unawareness. Women are advised to notify their physician if they are breastfeeding, pregnant or planning to become pregnant. Possible side effects include hypoglycemia, nausea, decreased appetite, weight loss, vomiting, stomach pain, fatigue, dizziness or indigestion. The maker of pramlintide advises patients to perform glucose monitoring before and after every meal and at bedtime.

Because the various antidiabetic medications work in different ways, combinations of more than one drug can sometimes produce more effective treatment results. However, this benefit may also come with the added risk of increased side effects. Switching from one type of medication to another may not be as effective as adding another medication.

Combinations of antidiabetic agents that are prescribed include:

  • AGIs with biguanides or sulfonylureas
  • Biguanides with AGIs, DPP-4 inhibitors, incretins, meglitinides, sulfonylureas or TZDs
  • DPP-4 inhibitors with biguanides, sulfonylureas or TZDs
  • Incretins with biguanides, sulfonylureas or TZDs
  • Meglitinides and biguanides
  • Sulfonylureas with AGIs, biguanides, DPP-4 inhibitors or incretins
  • TZDs with biguanides, DPP-4 inhibitors, incretins or sulfonylureas

Some of these combinations are available in single pills marketed under various brand names.

In addition, insulin may be prescribed in tandem with other diabetes medications, including:

  • Biguanides
  • Sulfonylureas
  • Synthetic amylin
  • A TZD (although warnings for insulin/TZD combinations have become more restrictive)

A physician takes several factors into account before selecting a specific diabetic treatment option. Considerations about patients include:

  • Are they overweight?
  • Do they have abnormal cholesterol levels?
  • How is their kidney and liver function?
  • When did their diabetes develop?
  • How good are they about taking medications regularly?
  • Do they monitor glucose as instructed?
  • Do they have problems taking pills or making injections?
  • Do they already have a sensitive stomach?
  • What does their healthcare plan provide?
  • Are they prone to hypoglycemia (excessive drop in blood glucose levels, sometimes triggered by diabetes medication) or hypoglycemia unawareness?

Conditions treated with antidiabetic agents

The U.S. Food and Drug Administration (FDA) has approved oral antidiabetic agents and incretin mimetics to treat type 2 diabetes only, as a supplement to exercise and diet. Synthetic amylin is approved for cases of type 1 diabetes or type 2 diabetes that are already treated with insulin but need additional help controlling glucose (blood sugar).

Some physicians may choose to prescribe certain antidiabetic agents “off-label” for other conditions, such as prediabetes, insulin resistance or polycystic ovarian syndrome (PCOS).

Scientists are investigating possible additional uses of some antidiabetic agents. For example, cancer researchers are studying several potential roles for thiazolidinediones.

Conditions of concern with antidiabetic agents

Antidiabetic agents may cause additional risk for individuals who now or used to have certain health problems. Patients should inform their physician of these health conditions before undergoing treatment. Antidiabetic agents should not be used to treat diabetic ketoacidosis, according to the U.S. Food and Drug Administration. Additional conditions of concern may include:

  • Other endocrine disorders, such as thyroid, pituitary or adrenal disease
  • Kidney disorders
  • Liver disease
  • Heart conditions, including coronary artery disease and heart failure
  • Pregnancy
  • Severe injury, burn or infection
  • Major surgery
  • Osteoporosis

Conditions of concern vary according to the individual drug. Patients are advised to ask their physician about their particular medication and class of medications.

Potential side effects of antidiabetic agents

Hypoglycemia is the major side effect associated with some antidiabetic agents. This occurs when the medications cause glucose (blood sugar) levels to drop too low. Patients taking sulfonylureas, meglitinides or synthetic amylin are particularly susceptible to hypoglycemia.

Symptoms of hypoglycemia include:

  • Dizziness or lightheadedness
  • Hunger (polyphagia)
  • Nervousness or shakiness
  • Sleepiness or confusion
  • Sweating
  • Pounding of the heart (palpitations)

A side effect of concern for the majority of diabetic patients who are overweight or obese is weight gain. This can result from use of sulfonylureas, thiazolidinediones or meglitinides, as well as insulin.

Other side effects attributed to antidiabetic agents include:

  • A skin rash or itchiness
  • Headache
  • Metallic taste in the mouth
  • Flushing (especially after consuming alcohol)
  • Stomach discomfort, loss of appetite, gas and diarrhea
  • Nausea
  • Heartburn
  • Feelings of fullness
  • Edema (swelling)
  • Liver damage
  • Interference with the body’s absorption of iron
  • Anemia
  • Decreased bone density

Some diabetes mediations may help patients lose weight, a desirable effect for many but not all patients. These drugs include incretin mimetics, synthetic amylin, biguanides and alpha-glucosidase inhibitors.

The potential side effects of diabetes drugs vary widely according to the individual drug and the patient’s conditions. Patients are advised to ask their physician about their particular medication and class of medications.

Drug or other interactions

Patients receiving antidiabetic agents should consult their physicians before taking any additional prescriptions (including oral contraceptives), over-the-counter medications, nutritional supplements or herbal medications. A wide range of drugs and supplements ranging from corticosteroids to glucosamine and antidepressants to cinnamon capsules may affect glucose (blood sugar) in various ways.

Antidiabetic agents often interact well with other drugs, but there are many potential exceptions. For example, aspirin may interact with diabetes drugs including sulfonylureas, and the maker of the thiazolidinedione rosiglitazone does not recommend taking it with insulin or nitrates (a group of heart drugs) because this may increase the risk of heart problems. Patients are advised to ask their physician or pharmacist about interactions for their particular medication.

Patients should discuss alcohol consumption with their physician as alcohol can have a significant influence on medications, as well as on overall diet and health, including increased risk of hypoglycemia. Some diabetic patients are instructed by their physician not to drink any alcohol.

Pregnancy use issues with antidiabetic agents

Women who are pregnant are generally not prescribed oral antidiabetic agents. The amount of insulin a woman needs changes during and after pregnancy, and can best be controlled through a comprehensive physician-directed plan. Options for management include meal planning, exercise and insulin injections.

Pregnant women must maintain the proper blood glucose levels, as high blood glucose (hyperglycemia) can cause birth defects or excessive weight gain in babies.  Women who are pregnant or thinking of becoming pregnant should inform their physician immediately.

Some antidiabetic agents pass into human breast milk. Nursing mothers should consult with a physician before taking these medicines.

Child use issues with antidiabetic agents

Type 2 diabetes was rare in children until recent years. Metformin, a biguanide, was for years the only antidiabetic agent approved by the U.S. Food and Drug Administration (FDA) for children. In 2005, however, the FDA approved pediatric use of a sulfonylurea.

Clinical studies have been investigating possible pediatric use of other antidiabetic agents.

Elderly use issues with antidiabetic agents

Elderly patients are more vulnerable to side effects associated with some antidiabetic agents. They are particularly susceptible to hypoglycemia.

Ongoing research for antidiabetic agents

A great deal of research on potential drug treatments for diabetes is under way, including:

  • Incretin mimetics (GLP-1 agonists). Researchers are working on a longer-acting version of exenatide (Byetta) that could be injected only weekly instead of twice daily. Other incretins being assessed in clinical trials include liraglutide, which is also being studied as a potential treatment for obese nondiabetics, and albiglutide.
  • Weight-loss drugs. Studies have shown that rimonabant (Acomplia), in addition to helping patients lose weight, might help control glucose and improve cardiovascular health by reducing triglycerides and increased HDL “good” cholesterol. Rimonabant has been approved in the European Union, but concerns raised before the U.S. Food and Drug Administration (FDA) include possible psychiatric side effects such as depression and anxiety. For this reason, rimonabant is not currently available in the United States.

    Other drugs being studied to treat obesity and type 2 diabetes include cetilistat (a gastrointestinal lipase inhibitor), BAY 74-4113 (which also modifies the metabolism of lipids), appetite-controlling hormones such as leptin and ghrelin, and quercetin, a flavinoid (antioxidant plant pigment) found in food including apples and tea.
  • Vaccines. Clinical trials involving people with recent-onset type 1 diabetes have shown promise for Diamyd, a potential vaccination against diabetes. Diamyd appears to preserve beta cells in the pancreas and enhance their production of insulin. The vaccine may also help treat type 2 diabetes.
  • Insulin pills. Clinical trials are examining the effect of oral insulin tablets on people with type 2 diabetes.
  • Glitazars. The FDA appeared poised to approve muraglitazar (Pargluva), the first of a new class of antidiabetic agents called glitazars, after an FDA panel endorsed it in 2005. However, researchers then reported an increase of cardiovascular conditions including heart attack and stroke and a possible increased incidence of cancer in test subjects. Problems including cardiovascular side effects and lack of effectiveness have prompted discontinuation of several other glitazars that were under development, but some are still being researched.
  • Selective PPAR modulators. The goal of the non- thiazolidinedione metaglidasen is to control glucose and triglycerides without causing edema or weight gain. Other PPAR modulators being assessed in humans include PN2034 and harmine.
  • Anti-inflammatories. Some evidence suggests that chronic inflammation may be a factor in development of insulin resistance and type 2 diabetes. Researches are testing whether the nonsteroidal anti-inflammatory drugs (NSAIDs) salsalate or rofecoxib and anti-inflammatory monoclonal antibodies such as XOMA 052 may help. Researchers reported in 2007 that a short-term anti-inflammatory drug combination reversed new-onset type 1 diabetes in mice, and more research is planned.
  • Cardiovascular drugs. For example, the cholesterol drug colesevelam is being assessed for possible glucose-lowering effects in type 2 diabetes, and an investigational antihypertensive called AD-4833-536 is being assessed as a way to control glucose and blood pressure in people with type 2 diabetes and high blood pressure.
  • Cancer-fighting drugs. Angiogenesis inhibitors such as prinomastat are being studied as a way to slow the destruction of pancreatic beta cells in type 1 diabetes.
  • Gene regulators. A protein called calcineurin, recently found to regulate 10 genes linked to diabetes, and a related protein called NFAT are being investigated for possible pharmaceutical roles.
  • PBA and TUDCA. Research on animals suggests that chemicals known as PBA (4-phenyl butyric acid) and TUDCA (taurine-conjugated derivative) may improve levels of glucose and insulin and help fight fatty liver disease, a common condition in people with type 2 diabetes.
  • Vitamins. Researchers are examining whether vitamin D can prevent type 1 diabetes in children.
  • Carnitine. Scientists are studying whether oral supplements of carnitine, an amino acid derivative, may reduce hypoglycemia in children with type 1 diabetes.
  • Herbs and foods. Many herbs, spices, nuts and other foods are being investigated for possible glucose-controlling roles.

Researchers are also working on drugs to treat complications such as diabetic retinopathy and diabetic kidney disease.

Although pharmaceutical development is a long and complicated process, with frequent setbacks, scientists are reporting many encouraging results from laboratory studies and clinical trials.

Questions for your doctor on antidiabetic agents

Preparing questions in advance can help patients have more meaningful discussions with their physicians regarding their conditions. Patients may wish to ask their doctor the following questions about antidiabetic agents:

  1. Do I need to take antidiabetic agents, or am I likely to need medication soon?

  2. Which is the best class of drug or combination of drugs for me?

  3. How do my medications work?

  4. Can you recommend any diabetes drugs that may also help me lose weight?

  5. Do I have any conditions or am I using other medications that make it inadvisable to take an antidiabetic agent that was recommended for me?

  6. What is the name of my drug, the dosage and frequency? How and when should I take it?

  7. What should I do if I miss a dose or take too much?

  8. What are my chances of experiencing swelling, weight gain, nausea, dizziness or other side effects? At what point should I notify you of side effects?

  9. How do these medications affect my risk of hypoglycemia? What signs should I watch for and what action should I take if my blood sugar drops?

  10. Do I need to follow any dietary or exercise precautions when taking my medication?

  11. Can weight loss, exercise and diet reduce or eliminate my need for medication?

  12. What kind of monitoring will show if my dosage needs to be adjusted?

  13. Are my medications safe for children, pregnant women, breastfeeding women or elders?

  14. Do I also need to take insulin? Do I need medication for diabetic complications such as nephropathy, neuropathy or retinopathy? Do I need medication for blood pressure, cholesterol or obesity?

  15. Are antidiabetic agents an option for me if I’m not diabetic but have insulin resistance, prediabetes, polycystic ovarian syndrome or any other conditions?
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