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Sulfonylureas and the Risk of Cardiovascular and Hypoglycemia Events

Aug 18, 2018

Even as 2nd-line drugs, sulfonylureas shown to be cardiotoxic with high rate of low blood glucose

Sulfonylureas are used as second-line drugs or used in combination with other medications such as metformin for patients with type 2 diabetes. Metformin is the first-line agent used in type 2 diabetes. It is associated with a decreased risk of cardiovascular events and has a low rate of hypoglycemia. Sulfonylureas have been found to be cardiotoxic and have high rates of hypoglycemia. Although this holds true, these drugs remain the most commonly prescribed oral antidiabetic agents when metformin therapy fails or needs an additional medication for glucose control. In a population-based cohort study, sulfonylureas used as second-line drugs followed by metformin therapy were investigated to determine whether there was an increased risk of cardiovascular events and severe hypoglycemia in patients with type 2 diabetes.


The UK Clinical Practice Research Datalink (CPRD) is a large primary care database that contains the medical records for more than 14 million people. These medical records contain information such as diagnoses, procedures, medications, and anthropometric variables such as BMI, and social history, such as smoking and alcohol use. First, a base cohort was developed for patients who were diagnosed with type 2 diabetes and starting metformin therapy. The base cohort was done between April 1 1998 and March 31, 2013, and then followed up until March 31, 2014. Patients were excluded if they were under the age of 40 years old, had less than a year worth of history in the CPRD, or if the patient had polycystic ovarian syndrome. Patients already taking other diabetic medications were excluded as well. Patients who had a sulfonylurea added to their metformin therapy or those who switched from metformin to a sulfonylurea were identified. Each of these patients identified were then matched to a patient reference that remained on metformin-only therapy. These patients had to have received the same number of metformin prescriptions and started at the same time.

Patients were followed up until one of the following events occurred: treatment discontinuation, occurrence of a study outcome, or end of the study period. Treatment discontinuation was defined as an absence of a new prescription by the end of a 60-day period, or the addition or switch to a sulfonylurea or another antidiabetic drug. Reference patients who were on metformin monotherapy who needed the addition or were switched to a sulfonylurea were then matched to a reference patient on metformin monotherapy. Study outcomes included hospital admission for MI, hospital admission for ischemic stroke, death related to cardiovascular death, all-cause mortality, and severe hypoglycemia.

The cohort included 77,138 patients with their first prescription between April 1, 1998 and March 31, 2013. Of these patients, 25,699 were switched to a sulfonylurea or had one added to their metformin therapy during follow up. The mean follow-up was 1.1 years. During this time period, there was 337 myocardial infarctions, 299 ischemic strokes, 429 cardiovascular deaths, 1,190 deaths from any cause, and 150 severe hypoglycemic events. At baseline, patients in both the metformin monotherapy group and patients in the switched or add-on therapy group had similar profiles. When both groups were compared at follow up, the sulfonylurea group had increased risks for cardiovascular events and severe hypoglycemic events. When comparing patients who added a sulfonylurea to patients who were switched to a sulfonylurea, the patients who were switched were associated with increased risk of MI and increased risk of all-cause mortality.

There was no difference in the association of increased risk for ischemic stroke, cardiovascular death, or severe hypoglycemia. These outcomes most likely occur because of the side effect of sulfonylureas. For example, sulfonylureas cause weight gain, which increases the risk of myocardial infarction. Another side effect of sulfonylureas is hypoglycemia, which can cause arrhythmias to develop then lead to a stroke.

This study revealed an association between sulfonylureas and cardiovascular events and severe hypoglycemia. Whether the patient was adding a sulfonylurea to their metformin regimen or switching to a sulfonylurea as monotherapy, there is an increased risk for these events. Because metformin has cardioprotective properties, it is best to add the sulfonylurea to the regimen and keep the metformin therapy if possible.

Practice Pearls:

  • Metformin is the first-line agent used in type 2 diabetes.
  • Sulfonylureas are second-line oral antidiabetic drugs used in the treatment of type 2 diabetes.
  • Sulfonylureas can be used alone or in combination with metformin.
  • Although they are effective in lowering glucose, sulfonylureas have a side effect of hypoglycemia and can cause adverse events, such as cardiovascular events.
  • Because metformin is beneficial in cardiovascular health, a sulfonylurea should be added on to this regimen and continue metformin if additional glucose control is warranted.


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.” Bmj, 2018, doi:10.1136/bmj.k2693.

Amanda Cortes LECOM School of Pharmacy PharmD Candidate Class of 2019


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