Sulfonylureas – Beta Cell Stimulants

Sulfonylureas, the first drug group introduced into the U.S. in 1955, stimulates the beta cells to produce more insulin. These drugs have kept many Type 2’s off injected insulin. Sulfonylureas will not work in those with Type 1 diabetes (except for a specific type) nor in anyone with Type 2 whose beta cells no longer produce insulin. Loss of insulin production, indicated by a low C-peptide level in the blood, is found in those with Type 1 diabetes, in many who have Type 1.5 diabetes, and in many others with Type 2 diabetes for more than 6 to 15 years.

Target Organ: Pancreas
Action: Increase insulin release
Lowers HbA1c by 1% to 2%
Taken: with or without food
Drug Acts Over Dose Range Rel.Potency Doses/Day
1st Gen Orinase
6-10 hrs 500 – 3000 mg 1 2-3
100 – 1000 mg 3 1-2
24-72 hrs 100 – 500 mg 6 1-2
2nd Gen Glucotrol
12 hrs 2.5 – 40 mg 75 1-2
Glucotrol XL
(ext. rel. glipizide)
24 hrs 2.5 – 20 mg 150 1
Micronase, Diabeta
18-24 hrs 1.25 – 2.0 mg 150 1-2
(micronized gly.)
24 hrs 3 – 12 mg 250 1-2
3rd Gen Amaryl
24 hrs 1 – 8 mg 350 1
Side Effects: low blood sugar, bloating, nausea, heartburn, anemia, weight gain, sun sensitivity, metallic or change in taste in 1% to 3%
Contraindications: Type 1 diabetes, advanced liver or kidney disease, sulfa allergy

If the beta cells are able to produce insulin, this production can be increased by stimulating beta cells with certain medications such as the sulfonylureas and rapid insulin releasers (Prandin and Starlix). Insulin from the beta cells is released directly to the liver via the portal vein, allowing it to work more effectively.

Sulfonylureas can cause low blood sugars, although this occurs much less often than with insulin. Severe low blood sugars occur about 500 times more often with insulin than with sulfonylureas. Emergency room visits for low blood sugars occurred only once for every 4,000 person-years of sulfonylurea use during a large 10-year study done in Switzerland between 1975 and 1984. Low blood sugars brought on by sulfonylureas are generally infrequent and mild.

The original “first generation” sulfonylureas include Orinase (tolbutamide), Tolinase (tolazamide), and Diabinese (chlorpropamide). These drugs work well in lowering the blood sugar, but they have a major drawback. Because they bind to proteins in the blood, they can be dislodged by other medications that bind to these same proteins. Once dislodged, their activity can increase rapidly and lead to low blood sugars.

Diabinese lasts longer in the blood and on rare occasions can cause a severe and long-lasting form of hypoglycemia. Its use was phased out as newer, safer sulfonylureas became available. However, chlorpropamide, the generic form of Diabinese, can still be encountered in many nonprescription oriental “herb mixtures” that are imported and used as over-the-counter treatments for diabetes within the U.S. The product label is unlikely to list chlorpropamide, so the wise approach is to avoid the use of any herb mixtures for diabetes.

Second-generation sulfonylureas include Glucotrol (glipizide), as well as Micronase, Diabeta, and Glynase (all contain glyburide). A third-generation called Amaryl (glimepiride) is also available. These drugs have an advantage for those who use other medications since they do not bind to carrier proteins in the blood. Because of this, drug interactions that may cause low blood sugars are less likely.

Sulfonylureas work best when taken at the same time each day. Glyburide and glipizide are shorter-acting versions. Glyburide (Micronase and Diabeta), and glipizide (Glucotrol) are usually taken twice a day, half before breakfast and half before dinner. Sustained-release versions called Glynase or Glucotrol XL are also available. Long-lasting versions can be taken once a day instead of twice a day. These medications can be used once a day before the evening meal when a person has high blood sugars at bedtime or before breakfast if care is taken to monitor the daytime blood sugar until the safety of the dose is assured.

As well as stimulating insulin production, Amaryl (glimepiride) may cause a mild reduction in insulin resistance and may be less likely to cause low blood sugars than other sulfonylureas. It is also safer for people who have advanced kidney disease indicated by an elevated creatinine level. Other sulfonylureas are usually not recommended when the creatinine level is elevated. Glimepiride also does not block the normal relaxation of blood vessels and does not affect coronary arteries. These unwanted side effects may occur infrequently with other sulfonylureas.

When starting a sulfonylurea, the risk of a low blood sugar is greatest during the first few days to the first four months of use. Be careful during this time and check your blood sugar often when you exercise, increase activity, or skip a meal. Drinking alcohol or taking certain medications like decongestants can also increase the risk of a low. Medications, such as steroids, beta-blockers, niacin, and Retin-A may decrease the action of a sulfonylurea and cause the blood sugar to rise.

A Recent Study

A recent study has identified a genetic mutation, called KCNJ11, that prevents insulin-producing cells from releasing insulin. Dr. Andrew Hattersley of Peninsula Medical School in Exeter had been studying the genes of patients diagnosed with Type 1 diabetes before the age of six months. The reported occurrence rate of this type of diabetes is about 1 in 500,000 but it may be more.

Usually, when you have an elevated blood sugar from eating, your body closes a channel in the insulin-producing cells. This causes potassium to accumulate, which triggers another channel to open and release calcium. When the calcium flows into these cells, insulin is released. With the mutated gene, this potassium channel does not close so insulin is not released as it should be. However, giving a sulfonylurea medication that is normally used for Type 2 diabetes helps correct this defect by closing the potassium channel, stimulating the calcium release and the release of insulin.