The Declining Role of Sulfonylureas as Add-on Therapy in Diabetic Patients

Nicholas Ellis, PharmD Candidate; Marcus W. Campbell, PharmD, BC-ADM

Sulfonylureas are a class of medications commonly used in the treatment of type 2 diabetes mellitus; the second generation sulfonylureas currently used in practice include glimepiride, glyburide, and glipizide. These medications work by stimulating the pancreatic beta cells to secrete insulin, thereby lowering the body’s blood glucose level. Sulfonylureas have a history of effective use and provide a cost-conscious option for the treatment of type 2 diabetes. Traditionally, they are often used as first line adjunct therapy to metformin; however, as new research comes to light and newer agents emerge, sulfonylureas’ role as the “go-to” second line agent has been questioned.¹

In every diabetic patient, it is important to select an appropriate drug regimen during the early stages of the disease so as to prevent the need for insulin as long as possible. Unless otherwise contraindicated, metformin is the drug of choice for initial management.¹ Unfortunately, poor patient adherence or inadequate lifestyle changes decrease likelihood of monotherapy adequately controlling glycemic levels. It is important that clinicians are aware of appropriate adjunct therapy. Sulfonylureas have long filled this role, and understandably so based on their effectiveness in lowering HbA1c and low cost. When adherence is a concern, an affordable medication is a very attractive option. However, there are additional factors to consider, including side effects and other related outcomes.

Pancreatic beta cell apoptosis is a key factor in disease progression and poor long-term prognosis in diabetic patients. As the pancreas loses the ability to secrete insulin due to beta cell exhaustion, patients must rely on more aggressive therapy such as insulin. Sulfonylureas act upon these beta cells, and may accelerate this “burn-out” process. This mechanism is one of the main reasons widespread sulfonylurea use warrants caution. Within 1 to 2 years, sulfonylureas begin to lose their effectiveness, and in the process limit the extent of treatment sucess.^2,3

Additionally, sulfonylureas carry with them undesirable side effects, which can have a distinct influence on adequate control of the underlying diabetes. Most patients will experience weight gain after starting a sulfonylurea. This can have negative effects on a patient outcomes, such as circulatory problems. More importantly, hypoglycemia is a major concern in patients taking a sulfonylurea, especially longer acting options such as glyburide; glyburide has lost favor as an early stage option due to its pronounced risk of hypoglycemia and accompanying cardiovascular complications. Glyburide is included on the Beers List because the elderly are more likely to experience hypoglycemia, as well as show reduced renal function, which further increases the risk of hypoglycemia.^2,3,4

Risk of hypoglycemia should always be assessed when selecting any antihyperglycemic medication with insulin effects. The risk of hypoglycemia is one of the primary reasons to delay injectable insulin therapy for as long as possible. In several trials (ACCORD, ADVANCE, and VADT), hypoglycemic events resulted in increased all-cause mortality, particularly with cardiovascular events. This includes possible arrhythmias, QT prolongation, and poor myocardial infarction outcomes. For these reasons, the role of sulfonylureas in the treatment of diabetes should be reexamined.³

Sulfonylureas are currently a viable second-line agent for clinicians due to their pronounced A1c lowering effects and affordability. As newer agents begin to prove their effectiveness and improve their cost-effectiveness, we must consider these additional options.

References:

1. Garber AJ, Abrahamson MJ, Barzilay JI, Grunberger G, et al. AACE comprehensive diabetes management algorithm 2013. Endocrine Practice. 2013;19:327-335
2. Kumar, A. Second line therapy: type 2 diabetic subjects failing on metformin GLP-1/DPP-IV inhibitors versus sulfonylurea/insulin: For GLP-1/DPP-IV inhibitors. Diabetes Metab Res Rev. 2012.28(Suppl 2):21-25.
3. Cefalu, W. T., Buse, J. B., Del Prato, S., Home, P. D., et al. Beyond Metformin: Safety Considerations in the Decision-Making Process for Selecting a Second Medication for Type 2 Diabetes Management. Diabetes Care. 2014;37:647-2659.
4. The American Geriatrics Society 2012 Beers Criteria Update Expert Panel (2012), American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society. 2012;60:616–631.