October 22nd, 2013

Are Sulfonylureas Dangerous?

CardioExchange’s editors asked endocrinologist Dr. Kasia Lipska to share her thoughts about a presentation by Craig Currie at this year’s annual meeting of the European Association for the Study of Diabetes in Barcelona.

Dr. Currie, of Cardiff University, and his fellow researchers retrospectively analyzed data from the Clinical Practice Research Datalink (CPRD), which comprises about 10% of all primary care patients in the UK. Of roughly 92,500 patients with type 2 diabetes in the CPRD who started their diabetes treatment from 2000 to 2012, about 83% received metformin and about 17% received sulfonylureas as monotherapy. An analysis of two matched cohorts (metformin vs. sulfonylurea monotherapy), involving about 4000 patients who were directly matched and about 18,000 who were propensity-matched, showed that sulfonylurea recipients were 58% more likely to die from any cause than were metformin recipients (mean follow-up, 3 years).

In a press release, Currie made these two statements:

Mortality was significantly increased in patients prescribed sulfonylureas as first-line, glucose lowering monotherapy, compared with metformin monotherapy. Whilst residual confounding and confounding by indication may remain, this study indicates that treatment with first-line monotherapy with sulfonylureas should be reconsidered.

Not all general practitioners or other doctors are fully informed about the risks and benefits of commonly used drugs. Failure to identify the higher mortality associated with certain drugs could also be regarded as a failure of the regulatory system.


Metformin is widely regarded as a first-line treatment for patients with type 2 diabetes, given its favorable effects on glucose levels, weight, and cardiovascular events, as well as safety and cost. About 65% of U.S. patients who first start an oral agent for diabetes use metformin. But if metformin is contraindicated or not tolerated, sulfonylureas are considered a reasonable next choice. Given the findings by Dr. Currie and his colleagues, should this approach be abandoned?

Sulfonylureas are the oldest oral agents available for treatment of type 2 diabetes — the first-generation sulfonylureas became available in 1955. But despite 58 years of clinical use, I still find myself uncertain about the safety of this class of drugs. Head-to-head comparisons of diabetes therapies are simply lacking, leaving clinicians and patients without good evidence to inform treatment decisions.

In 1976, the University Group Diabetes Program (UGDP) trial reported an increased risk for cardiovascular death associated with the use of tolbutamide compared with placebo or insulin. Subsequently, the FDA mandated a black-box warning for all sulfonylureas. But the risk for cardiovascular death noted by the UGDP was not supported by the 1998 UK Prospective Diabetes Study, which showed no difference in cardiovascular risk between the use of sulfonylureas or insulin therapy but a benefit with the use of metformin. In fact, the 2008 ADVANCE study of intensive glucose lowering primarily used gliclazide in its intensive-glucose-control arm and found no cardiovascular risk associated with this strategy.

Craig Currie’s analysis undoubtedly bolsters the growing recognition that the exact strategy used for glucose lowering may actually matter. His data, supported by other analyses, do favor metformin over sulfonylureas with respect to safety and cardiovascular outcomes. I suspect that among the roughly 35% of patients who start treatment other than metformin as their first medication for diabetes, some could safely use metformin. But for those who can’t tolerate that drug or for whom it’s clearly contraindicated, what would you do?

Do sulfonylureas actually increase the risk for death, or is metformin protective? To what relative extents do the therapy used, the attributes of the patient, and the quality of the physician play a role? Unfortunately, until we have more trial data that directly compare glucose-lowering medications with respect to clinical outcomes, we will continue to ask these fundamental questions and go on operating in the dark.


Share your thoughts about the use of sulfonylureas in clinical practice, in light of Dr. Currie’s new research and Dr. Lipska’s analysis of it.

One Response to “Are Sulfonylureas Dangerous?”

  1. William DeMedio, MD says:

    Certainly there are dangers associated with sulfonylureas or any class of compounds that stimulate insulin release.They can cause fatal episodes of hypoglycemia as well as episodes of hypoglycemia that result in the release of beta adrenergic amines which subsequently sensitize the myocardium to ventricular dysrhythmias. This is what is most likely responsible for the increased mortality with these medications.

    In the short term however, the sulfonylureas are more effective at alleviating the symptoms of diabetes, and tend to be used in new onset type two diabetics with higher sugars that don’t respond to metformin. Sulfonureas are also used in people with heart failure, liver or renal disease where you can’t use metformin. People with these diseases start out with higher mortality risk than usual. This also raises the level of mortality in sulfonylurea users.

    There are numerous specific instances of patient or physician preference where the sulfonylurea is chosen first, be it cost, comfort, or comorbidity. A randomized controlled trial may give a broad statistical result from a large group of people regarding the “safer” therapy, but will not tease out the special instances where it is actually safer, more efficacious, cost effective, or a combination of all three to use a sulfonylurea.