Antidiabetic Drugs

Antidiabetic drugs are medications that work to lower blood glucose concentrations, or the amount of sugar in the blood. They are an important way of treating gestational, type 1 and type 2 diabetes mellitus. There are many types of antidiabetic drugs. Herbal remedies and other forms of alternative medicine are also used for diabetes treatment, especially in areas where modern drugs are not easily available.

Antidiabetic drugs exert their useful effects through: (1) increasing insulin levels in the body or (2) increasing the body's sensitivity (or decreasing its resistance) to insulin, or (3) decreasing glucose absorption in the intestines.

This page is an overview of the different diabetic drug classes.

Other Names

• Hypoglycemic agents
• Antidiabetes drugs
• Sugar pills
• Oral antidiabetic drugs (OADs)
• Diabetes drugs, diabetic drugs

Note: Both of the apparently contradictory terms diabetic drug and antidiabetic drug are sometimes used to refer to drugs used to treat diabetes. Here we are using the conventional prefix anti- to designate the class of drugs that opposes or reduces the effects of a condition.

Background: Blood Sugar and Measuring Levels

There are many different chemical compounds that are sugars, but in diabetes, the sugar molecule of interest is glucose. The terms blood sugar and blood glucose mean the same thing.

The amount of glucose, or sugar, in the blood is measured in milligrams per deciliter (mg/dL) or millimoles per liter (mmol/L). A normal blood sugar level in a healthy adult ranges from about 65–120 mg/dL.

Another way of measuring blood glucose is to check the glycated hemoglobin A1C level, which is measured as a percentage. This measurement, often called just A1C, is a way of telling what the average blood glucose has been for the last one to three months. Glycated hemoglobin is hemoglobin (the oxygen-carrying molecule) that has gradually become coated with sugarlike substances from too much sugar in the blood. In a healthy person, a normal A1C would be less than 4%. For people with diabetes, the American Diabetes Association (ADA) recommends that treatment aim for an A1C of 7% or lower. Antidiabetic drugs, along with diet and exercise, help achieve this goal.^[1]

Uses

Antidiabetic drugs are used to lower the concentration of glucose in the blood of people with diabetes mellitus. By keeping the blood sugar at or close to the normal range, these medicines reduce some of the risks associated with diabetes.

Antidiabetic drugs are not useful in the treatment of diabetes insipidus, which is a disease of urine production that does not lead to high blood sugar.

Types

There are numerous types, or classes, of antidiabetic drugs. Each class includes from one to several individual drugs.

Oral Medications

Different kinds of diabetes pills work in different ways to control blood sugar. If one pill is not working well enough on its own, your doctor or nurse may combine it with a second kind of pill. This chart shows the different kinds of diabetes pills and how they work.

Antidiabetic Drugs That Increase Insulin

Since the absolute lack of insulin (in type 1 diabetes) or the relative lack of insulin (in type 2 diabetes) is the basis of diabetes, insulin replacement or augmentation is an obvious approach to therapy.

• Insulin is a hormone produced by the pancreas. The discovery and commercialization of insulin therapy was a milestone in the history of 20th-century medicine and revolutionized treatment of the disease. Insulin is a small protein that must be injected or inhaled to be effective. By changing certain amino acids in the insulin molecule or changing how it is combined with carrier molecules, scientists have discovered many ways to speed up or slow down insulin's glucose-lowering effects. As a result, there are several forms of insulin on the market. Some act immediately after they are injected, while others act slowly over many hours. Examples include insulin glargine (Lantus, a slow insulin) and insulin lispro (Humalog, a fast insulin).

Insulin is the best-known antidiabetic drug. It is what the body uses naturally to control blood sugar levels. People with type 1 diabetes require insulin, since they make none (or almost none) of their own. Whether it is given by injection or inhalation, insulin is absolutely required for treatment of this form of the disease. By contrast, people with type 2 diabetes often take pills to control their blood sugar, and the pills may contain more than one type of active ingredient. After months (or years) with the disease, some people with type 2 diabetes may also need to inject insulin to achieve good blood sugar control.

Main Article: insulin therapy

• Sulfonylurea-type drugs lower blood glucose by causing the body to release stored insulin.^[2] There are several drugs in this class, which may be used alone or in combination with other antidiabetic drugs. They are not used for people with gestational diabetes or type 1 diabetes. Drugs in this class sometimes cause dangerously low blood sugar (hypoglycemia). Examples in this class of agents include glipizide (Glucotrol) and glyburide (Diabeta, Micronase, Glynase).

Main Article: Sulfonylurea

• Glitinides lower blood glucose by stimulating the body to release insulin, much like the sulfonylureas do.^[3] Examples include repaglinide (Prandin) and nateglinide (Starlix).

• Incretin mimetics are drugs that act in the pancreas to release stored insulin, but differ from sulfonylureas and meglitinides in that they only have this effect when glucose levels are high. This class of drugs is relatively new, and so far, drugs in this class must be injected to be effective. Exenatide (Byetta) is very similar to the incretin known as GLP-1, and a very similar drug, Liraglutide, may be available soon. In addition to helping control blood sugar, incretin mimetics are also associated with weight loss and may be associated with increases in the number of insulin-producing beta cells in the pancreas.^[4]

Antidiabetic Drugs That Increase Insulin Sensitivity

Another important abnormality in diabetes, especially type 2 diabetes, is that insulin does not work as well as it should. For a given amount of insulin, blood sugar does not decrease as it should. This is called insulin resistance, or a decrease in insulin sensitivity. Drugs that help overcome this problem are also known as insulin sensitizers.

• Thiazolidinediones, such as pioglitazone (Actos) and rosiglitazone (Avandia), work by increasing insulin sensitivity. Drugs in this class change the pattern of gene and protein expression in some cells that helps make organs such as the liver and muscle more sensitive to the effects of insulin.^[5]

• Metformin is a drug in the biguanide class that also acts to increase insulin sensitivity. It also reduces glucose production by the liver. Metformin is the most commonly-used agent for type 2 diabetes in children and teenagers and, unlike other antidiabetic drugs, tends not to cause weight gain. Metformin is especially well-suited for women with gestational diabetes.^[6]. The long history^[7], low price, and potential for weight loss with this drug contribute to its popularity. A brand name of metformin is Glucophage.

Antidiabetic Drugs That Decrease Glucose Influx

After a meal, nutrients in the intestine are absorbed into the blood, from where they are eventually either used or stored. Antidiabetic drugs in this category work by slowing down the rate at which nutrients—especially glucose—move from the inside of the intestine (the intestinal lumen) to the blood.

• Alpha-glucosidase inhibitors work in the small intestine by inhibiting a digestive enzyme known as alpha-glucosidase. Drugs such as miglitol (Glyset)^[8] and acarbose (Precose) are in this class. They have unpleasant side effects such as flatulence and bloating, but acarbose has been shown to provide significant cardiovascular benefits.^[9]

• Amylinomimetics work by replicating the effects of amylin, a hormone from the pancreas that is released along with insulin. Pramlintide (Symlin) is the only drug in this class. One of pramlintide's main effects is slowing the rate at which food leaves the stomach; this results in lower postprandial (after-eating) spikes in blood glucose concentrations.^[10]

Antidiabetic Drugs That Decrease The Liver's Glucose Output

Glucose can enter the blood from the intestines (as it does after a meal), or it can be released from storage pools in the liver during times when the intestines are relatively empty. Hepatic glucose output refers to the glucose released from the liver. Glucose molecules released in this way usually come from the liver's stockpile of glycogen, a special molecule made of hundreds to thousands of glucose molecules linked end-to-end for energy storage.

• Incretin mimetics are discussed above. Drugs such as exenatide act on the liver to reduce the amount of glycogen that is converted to glucose/

• DPP-4 inhibitors, or dipeptidyl peptidase IV inhibitors, work by enhancing or prolonging the effects of a substance in the body called GLP-1, and in this way they indirectly inhibit the conversion of glycogen to glucose.

• Insulin has many effects, including a direct effect on the liver to reduce the amount of glycogen turned into glucose.

• Thiazolidinediones, metformin, and amylinomimetics also work in the liver to decrease glucose output.

Antidiabetic Drugs That Sequester Bile Acids

Drugs that sequester, or capture, bile acids were developed to reduce high levels of LDL in people with hypercholesterolemia but have recently been shown to reduce blood glucose levels in patients with type 2 diabetes. This reinforces the idea that many of the body's control systems overlap.^[11] The drug colesevelam was recently approved by the FDA to help control blood glucose in this condition.^[12]

Alternatives To Antidiabetic Drugs

While antidiabetic drugs provide a wide range of generally safe and reliable ways to control diabetes, there are alternatives that may reduce the need for them. Caloric restriction and increased physical activity not only help diabetic patients maintain normal blood glucose values, they also can delay or prevent some people from developing diabetes in the first place.

Alternatives to drug therapy for type 1 diabetes

People with type 1 diabetes, especially those who are unaware of hypoglycemia, may be candidates for curative therapy in the form of a pancreas transplant. This is a difficult and expensive procedure that requires significant after-surgery medical care. Continuing research efforts that are focused on transplanting the insulin-producing cells (the beta cells), rather than the entire pancreas, may result in safe and effective therapies or cures for this disease.

References

1. ↑ Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ. 2005 Jan 18;172(2):213-26. Abstract | Full Text | PDF
2. ↑ Proks P, Reimann F, Green N, Gribble F, Ashcroft F. Sulfonylurea stimulation of insulin secretion. Diabetes. 2002 Dec;51 Suppl 3:S368-76. [1] | Full Text | PDF
3. ↑ Blicklé JF. Meglitinide analogues: a review of clinical data focused on recent trials. Diabetes Metab. 2006 Apr;32(2):113-20. Abstract | Full Text | PDF
4. ↑ Chia CW, Egan JM. Special Features: Incretin-Based Therapies in Type 2 Diabetes Mellitus. J Clin Endocrinol Metab. 2008 Jul 15. Abstract | PDF
5. ↑ Tack CJ, Smits P. Thiazolidinedione derivatives in type 2 diabetes mellitus. Neth J Med. 2006 Jun;64(6):166-74. Abstract | PDF
6. ↑ Lundberg GD. Metformin trumps insulin in the treatment of gestational diabetes.Medscape J Med. 2008 Jul 31;10(7):179. Abstract | Full Text
7. ↑ Lefèbvre P. Metformin, fifty years since the arrival of this molecule! Journ Annu Diabetol Hotel Dieu. 2007:1-3. (in French) [http:/pubmed.gov/18613324 Citation]
8. ↑ Campbell LK, Baker DE, Campbell RK. Miglitol: assessment of its role in the treatment of patients with diabetes mellitus.Ann Pharmacother. 2000 Nov;34(11):1291-301. Abstract
9. ↑ Hanefeld M, Schaper F. Acarbose: oral anti-diabetes drug with additional cardiovascular benefits. Expert Rev Cardiovasc Ther. 2008 Feb;6(2):153-63. Abstract
10. ↑ Pullman J, Darsow T, Frias JP. Pramlintide in the management of insulin-using patients with type 2 and type 1 diabetes. Vasc Health Risk Manag. 2006;2(3):203-12. [2] | Full Text | PDF
11. ↑ Goldfine AB. Modulating LDL cholesterol and glucose in patients with type 2 diabetes mellitus: targeting the bile acid pathway. Curr Opin Cardiol. 2008 Sep;23(5):502-11. Abstract
12. ↑ Goldberg RB, Fonseca VA, Truitt KE, Jones MR. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med. 2008 Jul 28;168(14):1531-40. Abstract