Sulfonylureas – Beta Cell Stimulants

Sulfonylureas, the first drug group introduced into the U.S. in 1955, have fallen out of favor for treating diabetes. They work by stimulating the beta cells to produce more insulin. Unfortunately, they stimulate beta cells that are already over-stimulated in those who have insulin resistance. These drugs have kept many people with Type 2 diabetes temporarily off injected insulin. Unfortunately, this delays the start of insulin and medications that actually preserve insulin production. Once insulin is finally started, the severity of beta cell loss is more advanced. Check these links for more about today’s preferred medications, including insulin sensitizers (like Actos), GLP-1 agonists (like Ozempic, Trulicity, and Victoza), and SGLT2 antagonists (like Jardience, Farxiga, and Invocana). These newer medications are now preferred for initial treatment of Type 2 diabetes.

Sulfonylureas will not work in those with Type 1 diabetes, except for one rare and specific type, nor in anyone with Type 2 once beta cell production of insulin falls. Loss of insulin production, indicated by a low C-peptide level in the blood, is found in most people with Type 1 diabetes, in many with Type 1.5 diabetes, and in those with Type 2 diabetes for more than 6 to 15 years.. GLP-1s, interestingly, prolong bets cell health and insulin production.

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 can 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 an extensive 10-year study 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 significant drawback. Because they bind to proteins in the blood, their activity rapidly escalates and leads to low blood sugars when other compounds displace them. Displacement rapidly increases its activity and can 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” imported and used as over-the-counter treatments for diabetes within the U.S. The product label is unlikely to list chlorpropamide. Hence, the wise approach is to avoid the use of all non-standard herb mixtures designated for treating diabetes.

Second-generation sulfonylureas include Glucotrol (glipizide) and Micronase, Diabeta, and Glynase that 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 the blood’s carrier proteins. 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 a half before dinner. They can be taken before the evening meal if bedtime blood sugars are highest or before breakfast if after breakfast or before dinner are highest. Sustained-release versions called Glynase or Glucotrol XL are also available are available for once a day dosing. Monitor daytime blood sugars with a CGM or meter until their safety 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 avoided when the creatinine level is elevated. Glimepiride does not block the relaxation of blood vessels and does not affect coronary arteries. These unwanted side effects may infrequently occur with other sulfonylureas.

When starting a sulfonylurea, the risk of low blood sugar is highest during the first few days to the first four months of use. Be careful during this time and check your glucose often, especially 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 glucose. Medications, such as steroids, beta-blockers, niacin, and Retin-A, may decrease a sulfonylurea’s action and cause 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 studied 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 pathway to open and release calcium. When the calcium flows into these cells, insulin is released. This potassium channel does not close with the mutated gene, so insulin is not released as it should be. However, giving a sulfonylurea medication that is typically used for Type 2 diabetes helps correct this defect by closing the potassium channel, stimulating the calcium release, and releasing insulin.