Sulfonylureas: Uses, common brands, and safety info

In the 1930s, it was discovered that a synthetic sulfur compound used to treat typhoid fever caused patients’ blood sugar to fall significantly, a condition known as hypoglycemia. It was later confirmed that the sulfur compound caused the release of insulin from the pancreas, resulting in low blood glucose levels in typhoid patients. Insulin is a naturally occurring hormone that helps the body regulate blood glucose levels and provides cells with energy.

Diabetes mellitus is a condition in which the body’s ability to produce insulin is impaired, resulting in high blood glucose levels (hyperglycemia). In Type 2 diabetes, the pancreas may still make insulin, but it may not be in sufficient amounts to control the level of blood glucose in the body. Researchers found that when Type 2 diabetes patients were given the sulfur compound, a member of a class of drugs known as sulfonylureas (SUs), it stimulated the pancreas to produce more insulin to help reduce the high blood glucose levels to more normal levels.

In the 1950s the first SU, tolbutamide, was approved for use in Type 2 diabetes care followed by the introduction of several more drugs in the sulfonylurea class. Today, SUs are widely used since they are generally safe, effective, and inexpensive. This table lists commonly used SUs followed by information on how they work, what conditions they treat, safety, and cost.

Other sulfonylureas

• Tolazamide

Sulfonylurea combinations

• Duetact (pioglitazone/glimepiride)

• Glipizide/metformin

• Glucovance (glyburide/metformin)

What are sulfonylureas?

SUs are a class of drugs widely used in the management of Type 2 diabetes. They have been available in the U.S. for more than 60 years, beginning with the approval of Orinase (tolbutamide) by the U.S. Food and Drug Administration (FDA) in 1957. In 1984, a group of more potent second-generation SUs—Glynase (glyburide) and Glucotrol (glipizide)—were introduced. In 1995, the FDA approved a third-generation SU, Amaryl (glimepiride). 

SUs are generally thought to be safe and effective and are among the cheaper antidiabetic drugs available. The incidence of hypoglycemia, or low blood glucose, is a common side effect and may limit their use to some degree in favor of newer, different classes of antidiabetic drugs. 

How do sulfonylureas work?

In most patients with Type 2 diabetes, the pancreas still produces insulin, however, it does not make enough insulin or the body does not use it effectively which causes blood glucose levels to rise. SUs increase the release of insulin by stimulating the pancreatic beta cells. SUs are most effective in the earlier stages of Type 2 diabetes when there is still plenty of active beta cells in the pancreas. The effects of sulfonylureas may also help reduce blood glucose levels by improving the ability of insulin receptors on the body’s cells to use the insulin that is present.

What are sulfonylureas used for?

SUs are approved as an adjunct to diet and exercise to improve blood glucose control in adults with Type 2 diabetes.

RELATED: What are carbohydrates?

Types of sulfonylureas

SUs are generally classified into three groups, or “generations.”

First-generation sulfonylureas

The first SUs approved, which include Orinase (tolbutamide) and Tolinase (tolazamide), are known as first-generation SUs. While they are effective in lowering blood glucose levels, they do have some significant drawbacks including rare but significant liver toxicity. First-generation SU use has been largely replaced by second-generation agents.

Second-generation sulfonylureas

Second-generation SUs include Glucotrol (glipizide) and Glynase (glyburide). These have shown an advantage because they are more potent and can be given as a once-daily dose. Second-generation SUs are less likely to result in drug-drug interactions that lead to hypoglycemia, or low blood glucose levels, that may occur with the first-generation SUs.

Third-generation sulfonylurea

A third-generation SU introduced in 1995, called Amaryl (glimepiride), is even less likely to cause low blood glucose levels than other generations of SUs. Glimepiride may also cause the release of more insulin from the pancreas than some of the older agents.

Who can take sulfonylureas?

Adults

SUs are approved as an adjunct to diet and exercise to improve glycemic control in adults with Type 2 diabetes.

Children

The efficacy and safety of SUs have not been fully evaluated in pediatric patients with Type 2 diabetes and their use is not recommended in children or adolescents.

Seniors

Although there have not been overall differences seen in the effectiveness and safety of SUs in older patients, older patients are more susceptible to problems of low blood glucose (hypoglycemia). Because hypoglycemia is often more difficult to recognize in seniors, starting and maintenance dosing should be conservative to avoid low blood glucose levels. Older patients are more likely to have reduced kidney function, which may put them at an increased risk of experiencing low blood glucose levels. The American Diabetes Association recommends SUs should not be prescribed to older adults who live alone, have unreliable food intake, or lack a support system.

Are sulfonylureas safe?

Hypoglycemia

Sulfonylureas are generally well tolerated. The most common adverse effect of SUs is hypoglycemia, which is when blood glucose levels have fallen low enough, usually below 70mg/dL, that action is necessary to bring blood glucose levels back to a normal range. Hypoglycemia may last for several hours and severe hypoglycemia may even require medical treatment.

The signs and symptoms of hypoglycemia may include:

• Irregular or fast heartbeat

• Fatigue

• Pale skin

• Shakiness

• Anxiety

• Sweating

• Hunger

• Irritability

• Tingling or numbness of the lips, tongue, or cheek

Worsening hypoglycemia signs and symptoms may include:

• Confusion, abnormal behavior, or both, such as the inability to complete routine tasks

• Visual disturbances, such as blurred vision

• Seizures

• Loss of consciousness

Hypoglycemia in older patients may be more frequent and dangerous. As those with Type 2 diabetes age, their ability to recognize the symptoms of hypoglycemia may decrease and they may experience very low blood glucose levels without knowing it and fail to get immediate help.

Even though all SUs may cause hypoglycemia, the risk of hypoglycemia is higher when taking the longer-acting SUs such as Glucotrol XL (glipizide extended-release). Hypoglycemia typically occurs as a result of taking an excessive dose, after exercising, or if a meal is missed.

The best way to prevent hypoglycemia is to start SU therapy at the lowest recommended dose. Then the healthcare professional can increase the dose at intervals of two to four weeks until the desired blood glucose levels are reached. It is important to self-monitor blood glucose levels routinely to reduce the chances of experiencing a hypoglycemic event.

Weight gain

SUs are very commonly associated with weight gain. While the exact reason is unknown, it is commonly thought that an increase in between-meal snacking to avoid hypoglycemia may be one contributing factor. The degree of weight gain may also be related to the “generation” of SU prescribed, as Glynase (glyburide) is associated with greater weight gain than Amaryl (glimepiride) or Glucotrol (glipizide). Fortunately, weight gain is preventable when the SU is combined with another diabetes medication called metformin.

Cardiovascular events

Weight gain, fluid retention, and hypoglycemia are all cardiovascular risk factors. Some studies have warned that SUs may be associated with cardiovascular events, including increased mortality, and may also be associated with poorer outcomes following a heart attack (myocardial infarction). Although only one drug in the SU class (tolbutamide) was implicated, care must be taken since this warning may also apply to other SUs.

RELATED: Can hypoglycemia occur without diabetes?

Recalls

There are no current SU recalls as of April 2021. 

Restrictions

Patients with sulfa allergies or any other known hypersensitivity or allergies to the ingredients should avoid SUs.

Diabetic ketoacidosis should be treated with insulin and not a sulfonylurea.

Sulfonylureas do not treat Type 1 diabetes mellitus.

RELATED: Type 1 vs. Type 2 diabetes mellitus

Can you take sulfonylureas while pregnant or breastfeeding?

First-generation sulfonylureas are not recommended for use during pregnancy as there are concerns regarding fetal hypoglycemia and birth defects. High blood glucose levels during pregnancy are associated with an increased number of birth defects leading many experts to recommend insulin to maintain blood glucose levels. There are studies supporting the use of Glynase (glyburide) combined with metformin for the management of pregnant women with Type 2 diabetes as well as for women who develop diabetes during pregnancy (gestational diabetes).

Studies have determined that the transmission of second-generation SUs, such as Glynase (glyburide) and Glucotrol (glipizide), through breast milk to infants is minimal. The benefits provided by these medications seem to outweigh the small risk of the low presence of the drugs in breast milk. However, breastfed infants of lactating women using SUs should be monitored for symptoms of hypoglycemia.

Are sulfonylureas controlled substances?

No, sulfonylureas are not controlled substances.

Common sulfonylurea side effects

The following are potential common side effects when taking SUs. This is not an exhaustive list and you should always talk to your healthcare professional and seek medical advice about what side effects to expect and how to address them.

• Nausea

• Hypoglycemia (low blood glucose levels)

• Dizziness

• Nervousness

• Tremor

• Flatulence

• Headache

• Drowsiness

• Rash

• Pruritus (itching)

• Photosensitivity (increased sensitivity to sunlight)

How much do sulfonylureas cost?

SUs have a wide price range depending on the specific drug, quantity, and dosage. Since most SUs are available in generic form, they are much less expensive than the brand-name counterpart. For example, glipizide ER 10 mg a day costs about $28 a month. The brand-name version, Glucotrol XL, costs about $116 a month. A SingleCare card could reduce certain prescription costs up to 80% at participating pharmacies.