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People with Type 2 at Risk with Use of Sulfonylureas as Second-Line Medication

Dec 15, 2018
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Melissa Bailey, Pharm.D. Candidate, USF College of Pharmacy

Drugs shown to increase risk of hypoglycemic and cardiovascular events.

According to the 2018 American Diabetes Association guidelines, sulfonylureas are used in combination as second-line treatment with metformin and lifestyle management when patients are not at risk for atherosclerotic cardiovascular disease (ASCVD). Metformin remains first-line in patients with T2DM due to the low risk of cardiovascular events and decreased risk of hypoglycemia. Sulfonylureas tend to be one of the most commonly prescribed oral antidiabetic medications after failed treatment with metformin, despite the serious side effects that were found with sulfonylureas.


There are not many studies evaluating second-line medications as mono or additive therapy in relation to cardiovascular and hypoglycemic events. Most observational studies that have occurred only compare second-line medications for diabetes (i.e. dipeptidyl peptidase-4 inhibitors and insulin) in addition to metformin. Those studies have also shown to have limitations due to residual confounding and bias when selecting medications.

Dr. Samy Suissa and colleagues recently conducted a population-based cohort study in the United Kingdom to assess whether adding a sulfonylurea or changing from metformin to a sulfonylurea as monotherapy would have an impact on cardiovascular health and hypoglycemia. They reviewed health records from over 77,000 patients with T2DM who began metformin therapy between 1993 and 2013. Out of those 77,000 patients, about 24,500 changed to or added sulfonylureas. When compared to those who continued metformin as monotherapy, patients taking sulfonylureas were associated with a greater risk of having a myocardial infarction (HR 1.26, 95% CI) or  ischemic stroke (HR 1.24, 95% CI), and had an increased likeliness of dying from any cause (HR 1.28, 95% CI). Patients were more likely to have a hypoglycemic event as well (HR 7.60, 95% CI). When adding sulfonylurea therapy to metformin treatment, no differences were noted for stroke, heart disease, or hypoglycemia.

Patients with diabetes are at a higher risk of having a cardiovascular event, regardless if they are taking sulfonylureas or not. However, this study was able to show a statistically higher rate of risk with sulfonylureas vs metformin as monotherapy due to its large population size (77,000 patients). The study mentions that a main reason for cardiovascular events may be due to weight gain caused by the sulfonylurea.

According to the American Association of Clinical Endocrinologists  (AACE), sulfonylureas should be used as last line as there are much better alternatives out there, such as SGLT-2 inhibitors and GLP-1 agonists (i.e. Trulicity, Victoza, Jardiance).

Dr. Richard Bernstein, a well-known diabetes educator and MD, has not prescribed sulfonylureas in 20 years. He finds sulfonylureas to be best used as short-term therapy, if at all. Despite the known risk, primary care physicians seem to keep prescribing these medications, due to the ease of taking them in a pill form and their low cost. Dr. Suissa highly recommends having patients talk with their health care providers if they are taking a sulfonylurea as monotherapy for the treatment of diabetes.

Practice Pearls:

  • Sulfonylureas are not recommended as monotherapy due to the increased risk of stroke, heart attack, and all-cause mortality.
  • Sulfonylurea therapy has also been linked to more hypoglycemic events when used as monotherapy.
  • Better health outcomes were linked to patients who were using sulfonylureas as additive therapy to metformin.
  • According to the most recent ADA guidelines, metformin remains first choice as monotherapy in patients with type 2.


American Diabetes Association. Improving Care and Promoting Health in Populations: Standards of Medical Care in Diabetes-2018. Diabetes Care. 41.Supplement 1 (2018): S7-S12. doi: 10.2337/dc18-S001

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 362 (2018): k2693. PMC. Web. Aug. 2018.

Melissa Bailey, Pharm.D. Candidate, USF College of Pharmacy