BARCELONA, Spain (updated September 27, 2013) — First-line therapy with sulfonylureas significantly increases the risk for death in patients with type 2 diabetes when compared with treatment with metformin, a new study shows. Additional research showed that the combination of metformin and a sulfonylurea was also associated with a significantly increased risk for death when compared with combination therapy with metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor (or "gliptin").

Presenting the results of both studies to the media during the European Association for the Study of Diabetes (EASD) 2013 Meeting, Craig Currie, PhD, from the University of Cardiff, United Kingdom, said the findings should be a wake-up call to physicians and authors of clinical guidelines about the hazards of prescribing sulfonylureas to diabetic patients.

"I am bewildered it's still being used," Dr. Currie told Medscape Medical News. "People should avoid using a drug where the balance of evidence, at the moment, demonstrates that it kills people."

To Medscape Medical News, Andreas Pfeiffer, MD, from Charité Universitätsmedizin, Berlin, Germany, who moderated the EASD press conference, said sulfonylureas are used as first-line therapy in approximately 15% of patients, although use varies from country to country. Second-line treatment in Europe and North America typically includes sulfonylureas, however, because they are a very cheap and established treatment course and so are widely used as combination therapy with metformin.

"There has been a long discussion about this," said Dr. Pfeiffer. "The first study to highlight the risk was UKPDS in 1996, in which there was increased mortality in the combination group of metformin plus sulfonylureas. Since then, there have been about 25 papers saying why [the UKPDS] finding is not relevant, but now more signals are starting to emerge from other trials."

But Cornelius J. Tack, MD, from the Radboud University Nijmegen Medical Center, the Netherlands, told Medscape Medical News he is not overly concerned about this issue and will continue to routinely use sulfonylureas. "This is kind of an old story repeating," he observed. "Having been on various panels, I must say I am surprised by the widely held belief that sulfonylureas are dangerous. There are many countries that are convinced they are not good drugs, while there is not really the evidence for this."

Importantly, he adds, "Not all sulfonylureas are the same." There are clinical-trial data to indicate that gliclazide is safe, for example, he said, pointing to long-term outcomes from the ADVANCE study, which employed modified-release gliclazide.

Data From the CPRD

In the first new analysis reported at the EASD meeting, the researchers retrospectively analyzed the UK Clinical Practice Research Datalink (CPRD), a data set of more than 10 million patients that has been validated as representative of the UK population. In their assessment of the safety of sulfonylureas as a first-line therapy, they identified 15,687 type 2 diabetes patients treated with the drugs as monotherapy. As a comparison, they used 76,811 diabetic patients who were treated with metformin.

There were 13.6 deaths per 1000 person-years with metformin and 44.6 deaths per 1000 person-years with sulfonylureas. This translated into a 58% increased risk for all-cause mortality among diabetics treated with sulfonylureas as monotherapy.

During a press conference, Dr. Currie said that although sulfonylureas — such as glipizide, glyburide, and glimepiride — are not used often as first-line therapy, as they have largely been replaced by metformin, the present study showed that approximately 17% of patients sampled were still receiving them as monotherapy.

"There is quite a bit of literature that supports this thesis if you're looking," said Dr. Currie about the results. For example, a similar study of 23 000 patients presented at ENDO 2012 showed a similarly increased risk for death with glipizide, glyburide, and glimepiride compared with metformin. "It's just a little bit surprising that this isn't looked at more closely by the regulatory agencies," he continued.

In the second study, the researchers compared second-line combination therapy in 33,983 patients treated with metformin and sulfonylureas against combination therapy in 7864 patients treated with metformin and a DPP-4 inhibitor. In total, there were 16.9 deaths per 1000 person-years in the metformin/sulfonylurea patients and 7.3 deaths per 1000 person-years in the metformin/DPP-4 group. This translated into a 35% increased risk for all-cause mortality among those treated with metformin and sulfonylureas compared with the other group.

"In my view, the safety of sulfonylureas needs urgent evaluation, because we are potentially increasing the risk of all-cause mortality," said Dr. Currie. Regarding the combination-therapy data, he doubts the DPP-4s are "wonder drugs," but rather that the sulfonylurea added to metformin increases the risk in this particular combination.

Sulfonylurea Use Varies Worldwide

To the media, Dr. Pfeiffer said the clinical guidelines highlight the potential risks and benefits of sulfonylurea use in diabetic patients, but there are still a number of healthcare systems, such as that in Germany, that require doctors to prescribe sulfonylureas if a patient cannot take metformin or if a second drug is to be added.

Treatment cost is the main reason the drug class is still used frequently, because the newer DPP-4 inhibitors can cost €2 to €3 per day, adding up to hundreds every month, according to Dr. Pfeiffer. The analysis by Dr. Currie, he said, makes the treatment decision a little bit harder for healthcare systems to justify treatment with sulfonylureas.

Personally, Dr. Pfeiffer doesn't use the drug class any longer, as first-line or second-line treatment, something he is able to do because of greater freedom at his academic hospital. For Dr. Currie, treatment with pioglitazone is a much better option for combination therapy with metformin, although that drug is not freely available in all European countries, including France and Germany.

Dr. Tack said one of the ongoing cardiovascular-safety trials of a new diabetes drug, linagliptin (Tradjenta; Boehringer Ingelheim), will yield more data to inform this debate,

The Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA) study will directly compare the newer DPP-4 inhibitor with the older sulfonylurea in 6000 type 2 diabetes patients at high risk of cardiovascular disease receiving usual care

Dr. Currie reports research funding from Bristol-Myers Squibb and AstraZeneca. Dr. Tack reports having participated in advisory boards of AstraZeneca/Bristol-Myers Squibb, Johnson & Johnson, MSD, and Takeda and having received research grants from and lectured for Novo Nordisk.

European Association for the Study of Diabetes. Abstracts 200 and 201, presented Thursday, September 26, 2013.

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