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Higher Risks of Death and Heart Failure Tied to Sulfonylureas

Dec 8, 2009

Sulfonylurea monotherapy for Type 2 diabetes was associated with increased risks of all-cause death and congestive heart failure compared with metformin, a large, retrospective study showed.

According to Paul Elliott, MBBS, PhD, of Imperial College London, UK, through a mean follow-up of 7.1 years, both first-generation (HR 1.37, 95% CI 1.11 to 1.71) and second-generation (HR 1.24, 95% CI 1.14 to 1.35) sulfonylureas were associated with elevated mortality risks.

Second-generation drugs in that class were associated with an 18% higher risk of developing congestive heart failure (HR 1.18, 95% CI 1.04 to 1.34).

The findings are “consistent with the recommendations of the American Diabetes Association and International Diabetes Federation that favor metformin as the initial treatment for Type 2 diabetes,” the researchers wrote.

Commenting on the study, Vivian Fonseca, MD, of Tulane University in New Orleans, LA, pointed out several limitations inherent to this and other retrospective studies, including selection bias. He wrote in an e-mail that it is impossible to know the reasons individual patients were prescribed certain drugs.

For example, he wrote, high-risk patients with elevated creatinine will not be prescribed metformin, but might possibly receive a sulfonylurea instead. Because the patients are already at high risk, incident cardiovascular events cannot necessarily be blamed on the medication.

Some previous studies have suggested that certain oral diabetes drugs increase the risk of cardiovascular events, whereas others have failed to show a relationship.

To explore the issue, Elliott and his colleagues looked at data from 91,521 men and women with diabetes (mean age 65) from the U.K. General Practice Research Database. The patients’ glycosylated hemoglobin (HbA1c) levels ranged from 8.1% to 8.5%.

Three-quarters (74.5%) were being treated with metformin monotherapy. The next most common regimen (for 63.5%) was monotherapy with second-generation sulfonylureas.

Through a mean follow-up of 7.1 years, there were 3,588 incident myocardial infarctions, 6,900 cases of congestive heart failure, and 18,548 deaths.

The researchers examined the relationship of diabetes treatment with each of these events. Fully adjusted models controlled for sex, duration of diabetes, previous complications from diabetes, previous peripheral artery disease, previous cardiovascular disease, other medications, body mass index, cholesterol levels, systolic blood pressure, HbA1c, creatinine and albumin concentrations, and smoking status. None of the treatments included in the study had a significant association with risk of MI.

However, compared with metformin monotherapy, second-generation sulfonylurea monotherapy was linked to a greater risk of developing congestive heart failure (P=0.011).

Monotherapy with first- and second-generation sulfonylureas was associated with increased risks of all-cause death during follow-up (P=0.0003 and P<0.001, respectively).

Neither of the thiazolidinediones examined — pioglitazone (Actos) and rosiglitazone (Avandia) — were associated with risk of MI or congestive heart failure, compared with metformin monotherapy.

Pioglitazone either as monotherapy or in combination was associated with a significantly lower risk of all-cause mortality during follow-up, compared with metformin (HR 0.69, 95% CI 0.49 to 0.98).

There was some evidence of a higher mortality risk with rosiglitazone versus pioglitazone, but the difference was not statistically significant in the fully adjusted model.

“Overall, to date there is no clear or consistent evidence on the possible cardiovascular benefits or harms of rosiglitazone therapy, and results of clinical trials are awaited,” the researchers wrote in the journal article.

Practice Pearl:


Explain to interested patients that this retrospective study could not establish a causal relationship between any of the medications studied and adverse health outcomes.

Tzoulaki I, et al “Risk of cardiovascular disease and all-cause mortality among patients with Type 2 diabetes prescribed oral antidiabetes drugs: Retrospective cohort study using U.K. general practice research database” BMJ 2009; DOI: 10.1136/bmj.b4731.