Type 2 diabetes Patients who take metformin plus insulin at higher risk for heart disease, death

Patients with type 2 diabetes who take a combination of metformin plus insulin may be at higher risk for cardiovascular disease and death compared with those who take a combination of metformin plus sulfonylurea, according to a new study funded by the Agency for Healthcare Research and Quality (AHRQ) that appears in the June 11 issue of JAMA. The study, a review of medical records from national databases, found a greater association between insulin as a second-line treatment and risk of death and cardiovascular disease than sulfonylureas as second-line treatment.

Adults with type 2 diabetes are typically treated first with metformin, an oral medication that helps reduce elevated blood sugar. When combined with exercise and diet modification, metformin alone can help many patients control their blood sugar levels, keeping the disease in check. However, some patients require a second drug, usually an oral medication such as a sulfonylurea or a self-administered injection of insulin to bring their disease under control.

"Type 2 diabetes is a serious condition affecting millions of Americans, and they and their clinicians need good evidence to make informed decisions about the best treatment options," said AHRQ Director Richard Kronick, Ph.D. "The findings of this report may surprise those who had considered insulin to be a preferred secondary treatment for diabetes in most circumstances. However, consistent with AHRQ's mission, our goal is to generate evidence on critical treatment issues like this one and broaden the information available for patients and clinicians to use."

In the new study, AHRQ-funded researchers led by Christianne L. Roumie, M.D., M.P.H., of the Tennessee Valley Veterans Affairs Medical Center in Nashville, analyzed records from databases at the Veterans Health Administration (VHA), Centers for Medicare & Medicaid Services and the National Center for Health Statistics. They studied more than 42,000 patient records and the National Death Index to assess the effects of insulin and sulfonylureas, the two medications most commonly prescribed in the study population as second-line treatment for diabetes.

The retrospective cohort study compared 2,500 VHA patients who added insulin to their metformin regimen with 12,000 VHA patients who added a sulfonylurea. On average, patients were about 60 years old, and about 35 percent had history of heart disease or stroke. The patients studied had been on metformin for an average of 14 months, and their average hemoglobin A1c count (a key indicator of success in controlling blood sugar) was 8.1 percent, which is higher than is preferred, when the second medication was prescribed.

The researchers identified patients who were taking one of two drug combinations: metformin-plus-insulin or metformin-plus-sulfonylurea. Then they compared the risks of heart attack, stroke or death for these patients. They found an association of metformin-plus-insulin to have a higher risk of cardiovascular events and death than metformin-plus-sulfonylureas, although harms were found for both regimens. 

"Insulin has been shown to be a very good medication in achieving blood sugar control, and because of that, prior large studies have found that there is a reduced risk of developing diabetic kidney or eye disease," according to Dr. Roumie. "However, this study and others have shown that tighter glucose control doesn't necessarily have any benefit for heart disease, and these findings call into question recommendations that insulin is equivalent to sulfonylureas for most patients who can control their blood sugar with a second oral drug."

Dr. Roumie's research team also conducted a study published in 2012 on first-line treatments for adults with type 2 diabetes. In that study, which also was funded by AHRQ, the researchers compared the use of sulfonylurea with metformin for first-line treatment. They found that sulfonylureas, when used as a first-line treatment, increased patients' risk of death and cardiovascular events compared with metformin.

The new study looks only at second-line treatments. Together, these two studies of primary and second-line diabetes treatments can help clinicians better determine which medications are least risky for each patient, depending on the patient's clinical characteristics.

This study focused primarily on U.S. military veterans, and the study population was overwhelmingly white and male, so the study noted that there might be differences in the risks of using insulin as a secondary treatment in the broader population. As a retrospective analysis of VHA medical records, the study is not a randomized controlled trial and thus does not determine definitively that insulin directly led to deaths and cardiovascular disease. More research is needed to determine if these differences exist and, if so, to what extent, researchers said. Insulin is a powerful drug and is an appropriate treatment when patients cannot control their blood sugar with oral agents alone, researchers said.



Agency for Healthcare Research & Quality


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