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Sulfonylureas’ Association with Major Adverse Effects

Nov 16, 2019
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Taylor-Eugene Simmons, Florida A&M University, College of Pharmacy & Pharmaceutical Sciences, PharmD Candidate

Sulfonylureas’ adverse effects may mean that after almost 50 years, the age of sulfonylureas is coming to an end.

Sulfonylureas have been widely used in clinical practice for treatment of type 2 diabetes for nearly 50 years. With many newer drugs now available, sulfonylureas remain the most common anti-diabetic medications clinicians readily prescribe in addition to or after failure with first-line therapy drug metformin. The affordability and higher glucose-lowering efficacy are possible advantages that explain why this drug class is frequently used in practice. However, concerns have been raised for why sulfonylureas should not be used as first-line therapy, and should be avoided in use with metformin, due to concerns regarding severe cardiovascular and hypoglycemic risk.


The long-term safety of this class poses many questions for practicing clinicians.

Sulfonylureas are classified into two generations: first-generation and second-generation. Currently used are the second-generation sulfonylureas (Glyburide, Glipizide, Glimepiride, Glicazide), while the first-generation sulfonylureas are no longer used (Tolbutamide, Chlorpropamide, Tolazamide) due to severe hypoglycemia episodes. This drug class is typically used for patients with type 2 diabetes where cost is a major issue, patients who are not overweight, and for whom metformin is contraindicated, not well tolerated, or has failed to meet glycemic target goals. The most common adverse effects of sulfonylureas are hypoglycemia, weight gain, and risk for cardiovascular events. Clinicians initially prescribe lower doses of sulfonylureas to prevent the risks of hypoglycemia. Unfortunately, in some patients taking sulfonylureas, the adverse effects may outweigh the benefits.

Are the adverse effects of sulfonylureas serious and evident enough for practitioners to avoid usage? Multiple studies were done throughout the years, evaluating the use of sulfonylureas causing hypoglycemia. In a UK study, Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics databases to evaluate whether adding or switching to sulfonylureas is related to severe hypoglycemia while remaining on metformin as monotherapy in patients with type 2 diabetes. A total of 25,699 added or switched to sulfonylureas during the study. At the mean follow-up of 1.1 years, sulfonylureas showed an increase in hypoglycemia. Data resulted in an incidence rate of 5.5 vs. 0.7 per 1000 person-years, the hazard ratio of 7.60, and 95% confidence interval 4.64 to 12.44, which concluded a higher risk of patients experiencing hypoglycemia.

Also, cardiovascular risks have been associated with the use of sulfonylureas. The mechanism behind this rationale connects with the drugs binding to the SUR-1 receptor on pancreatic beta cells that leads to KATP channels closing, which in return raises the intracellular calcium. Theories have concluded the binding of the sulfonylureas to KATP channels in the cardiomyocytes affects the ischemic preconditioning, which can lead to myocardial infarction.  A US study examined the cardiovascular effects of all major second-line anti-diabetic medications in patients with type 2 diabetes who did not experience adequate glycemic control or could not tolerate metformin. The patients had commercial or Medicare Advantage insurance plans. 47.6% of the 132,737 participants filled prescriptions for sulfonylureas. They are comparing all the second-line therapy anti-diabetic medications to DPP-4 inhibitors due to the shown studies of neutrality in cardiovascular events. Results indicated the risks of cardiovascular events were much higher in sulfonylureas than DPP-4 inhibitors.

The current 2019 ADA guidelines conserve using sulfonylureas as last-line therapy if all other classes of anti-diabetic medications fail or if HbA1C is above the target goal unless cost is a major issue. When choosing a sulfonylurea to initiate, the ADA guidelines suggest choosing a second-generation (later) sulfonylurea due to a lower risk of hypoglycemia.

From the results, researchers have concluded that sulfonylureas are associated with serious life-threatening events that affect the decision to initiate these drugs. Assessing cardiovascular safety and hypoglycemic risk in sulfonylureas has been a major concern. Overall, an increased risk of these effects is related to introducing sulfonylureas into an anti-diabetic drug regimen. The undesired effects of sulfonylureas can potentially lead to health care providers not utilizing these drugs in the management of patients with diabetes.

Practice Pearls:

  • Sulfonylureas are effective in lowering HbA1C and are lower in cost for patients with diabetes, but the risk of cardiovascular events and hypoglycemia can outweigh the benefits.
  • The 2019 ADA Guidelines suggest using second-generation sulfonylureas due to lower risk of hypoglycemia.
  • Clinicians may consider prescribing GLP-1 receptor agonists, DPP-4 inhibitors, or SGLT-2 inhibitors more routinely after metformin rather than sulfonylureas due to increased risk of cardiovascular events.

Abrahamson, Martin J. “Should Sulfonylureas Remain an Acceptable First-Line Add-on to Metformin Therapy in Patients With Type 2 Diabetes? Yes, They Continue to Serve Us Well!” Diabetes Care, American Diabetes Association, 1 Jan. 2015 care.diabetesjournals.org/content/38/1/166,                                                                                                                            

Azoulay, Laurent, and Samy Suissa. “Sulfonylureas and the Risks of Cardiovascular Events and Death: A Methodological Meta-Regression Analysis of the Observational Studies.” Diabetes Care, American Diabetes Association, 1 May 2017, care.diabetesjournals.org/content/40/5/706.

Douros, Antonios, et al. “Sulfonylureas as Second-Line Drugs in Type 2 Diabetes and the Risk of Cardiovascular and Hypoglycaemic Events: Population-Based Cohort Study.” The BMJ, British Medical Journal Publishing Group, 18 July 2018, www.bmj.com/content/362/bmj.k2693.

Sola, Daniele, et al. “Sulfonylureas and Their Use in Clinical Practice.” Archives of Medical Science: AMS, Termedia Publishing House, 12 Aug. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4548036/.

Taylor-Eugene Simmons, Florida A&M University, College of Pharmacy & Pharmaceutical Sciences, PharmD Candidate