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An anti-diabetic drug or oral hypoglycemic agent is used to treat diabetes mellitus. They usually work by lowering the glucose levels in the blood. There are different types of anti-diabetic drugs, and their use depends on the nature of the diabetes, age and situation of the person, as well as other factors.
Insulin is the only non-oral antidiabetic drug. It is the mainstay of treatment in type I diabetes, in which insulin production is impaired. In type II diabetes, it is used when oral medication has become ineffective.
QUICK FIND (Note: Some information about drugs is contained on this page; more drug information can be found on other sites for which links have been provided under the "Quick Find" index below.
Blood Glucose Lowering Agents: Precose
Alpha glucosidase inhibitors are "diabetes pills" but not technically hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, so that glucose from the starch of a meal enters the bloodstream more slowly, and can be matched more effectively by an impaired insulin response or sensitivity. These agents are effective by themselves only in the earliest stages of impaired glucose tolerance, but can be helpful in combination with other agents in type 2 diabetes.
These medications are rarely used in the United States because of the severity of their side effects (flatulence and bloating). They are more commonly prescribed in Europe.
The medication class of thiazolidinedione was introduced in the late 1990s as an adjunctive therapy for diabetes mellitus (type II) and related diseases. The only registered use of the thiazolidinediones is in diabetes mellitus type 2 but it is being investigated experimentally in polycystic ovarian syndrome (PCOS) and non-alcoholic steatohepatitis (NASH). Several forms of lipodystrophy cause insulin resistance, which has responded favorably to thiazolidinediones. Thiazolidinediones, also known as "glitazones," bind to PPARγ, a type of nuclear regulatory protein involved in transcription of numerous genes regulating glucose and fat metabolism. They act as "insulin sensitizers" without increasing insulin secretion.
The main side-effect of all thiazolidinediones is fluid retention, leading to edema and potentially aggravating heart failure. Therefore, thiazolidinediones cannot be prescribed in patients with decreased ventricular function (NYHA grade III and IV heart failure)
Blood Pressure, Heart, Stroke & Lipid Profile Management
Pravachol(R) (pravastatin sodium) is used for reducing the risk of a stroke or a transient ischemic attack (TIA), otherwise known as a miniature stroke, in patients who have had a heart attack and have normal cholesterol levels (less than 240 mg/dl total cholesterol) and to reduce the risk of a recurrent heart attack and death from heart disease in this patient population. Pravachol therapy has been shown to reduce the risk of having a stroke in people who have had a heart attack and have normal cholesterol levels, even in those people who take aspirin.
Pravachol therapy is well tolerated by most patients. The most common side effects include mild skin irritation and transient rash and gastrointestinal upset. Pravachol should not be used by people with active liver disease or liver problems, in women who are pregnant or nursing, or people who are allergic to any component of the medication. Muscle pain or weakness could be a sign of a rare but serious side effect and should be reported to your doctor.
Meglitinides are related to sulfonylureas. The amplification of insulin release is shorter and more intense, and they are take with meals to boost the insulin response to each meal.
Adverse reactions include weight gain and hypoglycemia.
Biguanides reduce hepatic glucose output. Although it must be used with caution in patients with impaired liver or kidney function, metformin has become the most commonly used agent for type 2 diabetes in children and teenagers. The class of biguanide originates from the French lilac (Galega officinalis), a plant known for several centuries to improve the symptoms of diabetes mellitus (Witters 2001).
Metformin (Glucophage®, Fortamet®, Riomet®) is an anti-diabetic drug from the biguanide class (its other members are the withdrawn agents phenformin and buformin). Metformin should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast as patients are at an increased risk of lactic acidosis.
Uses - The main use for metformin is for the treatment of diabetes mellitus, especially when it is concomitant with obesity and insulin resistance.
It is also being used increasingly in polycystic ovary syndrome (PCOS) and non-alcoholic steatohepatitis, two other diseases that feature insulin resistance; these indications are still considered experimental.
Metformin is the only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with diabetes (UKPDS 1998).
Mechanism of Action - Despite its therapeutic benefits, the mechanism of action of metformin is uncertain. Its mode of action appears to be reduction of hepatic gluconeogenesis; the "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis. Metformin treatment reduces this by one third to two thirds. Zhou et al (2001) showed that metformin inhibits the hepatic enzyme AMP-activated protein kinase.
Side Effects - The most serious side effect of metformin is lactic acidosis. However, this complication is rare if the contra-indications are followed, as it seems limited to those with impaired liver and/or kidney function. The most common side effect of metformin is gastrointestinal upset. This includes diarrhea, cramps, nausea and vomiting. In a clinical trial of 286 subjects, 53.2% of the 141 who were given Metformin IR (as opposed to placebo) reported diarrhea, and 25.5% reported nausea/vomiting (source: Drug Facts & Comparisons 2005). The side effect of gastrointestinal upset can be source of severe discomfort for patients. It is very common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning and increasing the dose gradually. Gastrointestinal upset after prolonged, steady use is less common. For the relief of diarrhea and intestinal cramping, a small, non-prescription dose (~10mg) of codeine should be effective.
Contraindications - Metformin should not be used in any condition that may increase the risk of lactic acidosis. This includes heart failure, kidney disorders (creatinine over 150 μmol/l), lung disease and liver disease. Metformin should be temporarily discontinued before any radiographic procedure involving iodinated contrast (such as a CT scan or angiogram) as contrast may indirectly cause lactic acidosis due to temporary impairment of kidney fuction. Patients should always inform their physician if they taking metformin before consenting to any radiographic procedure.
Phenformin (DBI): used in 1960-1980s, withdrawn due to risk of lactic acidosis (up to 60 cases per million patient-years). In recent studies it was revealed that, as long as it is not prescribed to patients who are at risk, metformin is much safer, and the risk of lactic acidosis approximates that of people who are not on the medication (Salpeter SR et al 2003).
Insulin Sensitizing Drugs
Actos - Approved by FDA (1999) for type 2 diabetes; Takeda Pharmaceuticals America, Inc.’s and Eli Lilly & Co.’s. Also approved in Canada.
Actos(TM) (pioglitazone hydrochloride), is an oral treatment for type II diabetes in a class of insulin sensitizing diabetes agents known as thiazolidinediones (TZDs) and is always dosed once daily without regard to meals. As an adjunct to diet and exercise, Actos has four therapy indications: monotherapy and in combination with sulfonylureas, metformin or insulin to improve glycemic control in patients with type II diabetes.
In clinical research studies, Actos (45 mg) given once daily significantly lowered mean blood sugar levels (fasting blood glucose) in patients who were not previously taking anti-diabetes medications by 63.7 mg/dl as compared to baseline, which resulted in a difference of as much as 94.5 mg/dl, as compared to placebo.
Patients with type 2 diabetes often have high triglyceride levels and low levels of HDL or good cholesterol. These two abnormalities increase the risk for heart disease, especially in patients with diabetes. Importantly, compared with placebo, Actos significantly decreased mean triglyceride levels and increased mean HDL levels in both monotherapy and in combination with sulfonylureas, metformin or insulin. In contrast, no significant change in mean total cholesterol or mean LDL or bad cholesterol levels was seen with Actos used either as monotherapy or in combination therapy.
Side Effects: The majority of side effects reported during clinical trials were mild. The most commonly reported included symptoms of upper respiratory tract infection, headache, sinusitis, muscle pain, tooth disorder and sore throat. The number of patients who withdrew from clinical trials due to an adverse event while taking Actos was similar to or less than that taking placebo. As observed with other members of this class of drugs, weight gain has been noted. Additionally, mild to moderate edema and anemia have been reported in patients taking Actos. Patients receiving Actos in combination with insulin or sulfonylureas may be at risk for hypoglycemia and a reduction in the dose of insulin or sulfonylureas may be necessary. Occasionally, diabetes worsened during clinical trials. This occurred less frequently with Actos than with placebo. There have been no reported cases of jaundice or liver failure associated with Actos use in U.S. placebo controlled clinical trials. However, since liver toxicity has been observed with another drug in the TZD class, it is recommended that patients obtain medical monitoring of liver enzyme levels (via a routine blood test) prior to the start of therapy, every two months for the first year of therapy and periodically thereafter. In premenopausal anovulatory patients with insulin resistance, treatment with any thiazolidinedione may result in resumption of ovulation. These patients may be at risk for pregnancy.
Avandia - Approved by FDA (1999) for treatment oftType 2 diabetes as both monotherapy and in combination with metformin. SmithKline Beecham's and Bristol-Myers Squibb’s Avandia(R) (rosiglitazone maleate).
Avandia is a new thiazolidinedione (TZD), a class of novel, oral antidiabetic agents that treat the symptoms of type II diabetes and directly target insulin resistance - an underlying cause of the disease. Unlike most traditional diabetes drugs, Avandia helps the body's own insulin work more effectively, resulting in significant blood sugar control." A fundamental problem in type II diabetes is not a lack of insulin, but rather the body's failure to respond properly to its own insulin -- known as insulin resistance. Most older type II diabetes medicines work by increasing insulin production in the pancreas or decreasing glucose output through the liver, whereas Avandia sensitizes the body to use its own natural insulin more effectively.
The FDA approval was based on a review of data from clinical studies involving more than 5,500 patients with type II diabetes. In these studies, Avandia effectively lowered blood sugar levels of patients by up to an average of 76 milligrams per decilitre, as compared to placebo, and maintained blood sugar control for up to 12 months. Patients achieved an average reduction in Hemoglobin A1C (HbA1C) levels up to 1.5 percentage points at a daily dose of 8 mg, demonstrating a statistically significant improvement in glycemic control relative to placebo and also in comparison to baseline. Because of its high potency, only a small dose of Avandia is needed to achieve therapeutic control (4 mg/day and 8 mg/day).
Side Effects: Avandia was well-tolerated in clinical trials. Commonly
reported side effects with Avandia were upper respiratory tract infections and
headaches. As observed with other members of this class of drugs, weight gain
has also been reported. Additionally, anemia and edema have been reported in
patients taking Avandia. There have been no reported cases of drug-related
jaundice or liver failure in any Avandia clinical studies.
Side Effects and Contraindications - The withdrawal of troglitazone has led to concerns of other thiazolidinediones increasing the risk of hepatitis. Guidelines now mention that for the first year of thiazolidinedione therapy, a two- or three-monthly check of liver enzymes is conducted to ascertain that no liver damage is occurring.
Alpha Glucosidase Inhibitors
Blood Glucose Lowering Medications
Precose: Bayer Corporation, Pharmaceutical Division markets Precose (acarbose tablets) to be used in combination with insulin or metformin for patients with Type 2 diabetes. Insulin and metformin are drugs commonly used to treat Type 2 diabetes. (FDA Approval; 1999)
Precose may be added to the treatment regimen for patients whose Type 2 diabetes is inadequately controlled by insulin or metformin to further reduce both the postprandial (after meal) blood glucose spikes (levels) and the HbAlc (a measure of long term blood glucose control). As monotherapy, Precose works with the diet to reduce blood glucose levels in patients with Type 2 diabetes whose disease cannot be managed by diet alone. Precose works with the diet in the small intestine. Taken with the first bite of the meal, Precose’s unique mechanism of action delays carbohydrate digestion and glucose absorption. Precose specifically targets and lowers the sharp blood glucose spikes that occur after a meal (postprandial blood glucose.
Sulfonylureas and biguanides -- classes of drugs commonly used to treat diabetes -- typically lower fasting blood glucose but the hazardous postprandial glucose spikes persist in more than 60 percent of patients(1). Postprandial blood glucose spikes are a significant predictor of specific diabetic complications. Precose used as monotherapy does not cause hypoglycemia, hyperinsulinemia, weight gain or lactic acidosis.
Side Effects: Precose is contraindicated in patients with diabetic ketoacidosis, cirrhosis, inflammatory bowel disease, colonic ulceration, or partial intestinal obstruction. The most common side effects are flatulence, abdominal pain and diarrhea. However, some patients may benefit from a gradual dose titration to minimize gastrointestinal side effects.
Lebovitz HE. Therapy for Diabetes Mellitus and Related Disorders. 4th edition. Alexandria:American Diabetes Association, 2004.
Holland, Norman & Adams, Michael Patrick. Core Concepts in Pharmacology. Pearson Education, Inc. New Jersey. 2003.
Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Arch Intern Med 2003;163:2594-602. PMID 14638559.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65. PMID 9742977.
Witters LA. The blooming of the French lilac. J Clin Invest 2001;108:1105-1107. DOI 10.1172/JCI200114178.
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-1174. DOI 10.1172/JCI200113505.
Page Updated 01/06/2006