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Sandeep Singh Dhillon
Sulfonylureas for Diabetes Still Have a Role; Cost a Big Factor – Medscape
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SAN DIEGO — A talk on whether sulfonylureas still have a role in the contemporary treatment of type 2 diabetes garnered much interest here at the American Diabetes Association (ADA) 2017 Scientific Sessions.
Speaking to a large audience in a packed room, Kamlesh Khunti, MD, from the University of Leicester, United Kingdom, presented a fast-paced overview of the history of the use of sulfonylureas, randomized controlled trials vs observational data, mechanism of action, novel insights, and practical considerations.
While there is universal agreement that metformin should be the treatment of first choice in type 2 diabetes, there is still much debate about which of the many classes of drugs should be used second line, when metformin alone isn’t sufficient to control blood glucose.
“I don’t think you can throw away sulfonylureas completely; there are a lot of data showing that they can be beneficial, and a lot of it comes down to affordability,” Dr Khunti told Medscape Medical News following his talk.
There is extensive experience in using them, and the risks and benefits are reasonably well-understood, he stressed.
While the larger database studies may show that sulfonylureas are not as good as other type 2 diabetes drugs, in the randomized controlled trials, the data on efficacy, safety, and durability “are pretty reasonable….There is still a place for sulfonylureas…and in the UK, we still use them a lot,” he added.
On the other hand, “If affordability is not a problem, we don’t have a question,” he noted, implying that if cost were not a factor, he would choose a second-line agent other than a sulfonylurea.
Session chair Neda Rasouli, MD, University of Colorado, Aurora, told Medscape Medical News that with many newer class of medication to treat type 2 diabetes coming to the market, “some leaders in the diabetes field are saying that maybe there is no room for sulfonylureas.”
But “it’s hard to let them go because of the low cost,” she acknowledged, adding, “Everybody wants to make sure that they are using a medication that is safe, and that’s why I think there is great interest.”
However, “if cost werenot a factor, probably people wouldn’t use sulfonylureas,” she also acknowledged.

CAROLINA and GRADE Will Help Inform Choice

The extensive review presented by Dr Khunti at the ADA meeting showed that there are concerns about side effects such as hypoglycemia and weight gain with sulfonylureas, but the data were inconclusive about potential cardiovascular harm, Dr Rasouli noted.
Dr Khunti said: “We really need to [see] the head-to-head comparisons that we are all eagerly waiting for.”
These include data from the cardiovascular-outcome study of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (Tradjenta, Lilly/Boehringer Ingelheim) vs the sulfonylurea glimepiride in patients with type 2 diabetes (CAROLINA).
And findings from the Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes (GRADE) study. GRADE is comparing four commonly used diabetes medications — the sulfonylurea glimepiride, the DPP-4 inhibitor sitagliptin (Januvia, Merck), the glucagon peptide-1 (GLP-1) receptor agonist liraglutide (Victoza, Novo Nordisk), and insulin glargine — head to head, when added to metformin. Patients will be followed for 4 to 5 years, and “that study will help us to decide what the best medication is after metformin,” Dr Khunti noted.
Both studies are expected to complete their data collection for primary outcomes in February 2019 and August 2020, respectively, and the results will help guide clinical practice, Dr Rasouli agreed.
However, GRADE does not include sodium-glucose cotransporter 2 (SGLT2) inhibitors, and one of these agents, empagliflozin (Jardiance, Boehringer Ingelheim) was the first type 2 diabetes medication to show cardiovascular protection in the landmark EMPA-REG OUTCOME study reported in September 2015.
Two glucagon peptide-1 (GLP-1) agonists have since also shown this, liraglutide in LEADER and the investigational agent semaglutide (Novo Nordisk) in SUSTAIN-6.
“It will be interesting to see if other SGLT2 inhibitors and GLP-1 receptor agonists are cardioprotective,” Dr Rasouli commented to Medscape Medical News. “Then you might consider them as a second agent, but if [trials] don’t confirm it, then we go back to the costs of the medication.”She also noted that “right now, in the ADA guideline, basal insulin can be used after metformin, but there is clinical inertia, and not everybody is comfortable with starting an injectable therapy as a second agent.”
Can’t Ignore Cost When Considering Diabetes TherapiesStressing the importance of cost, Dr Khunti said: “Worldwide, 415 million people have diabetes, and 80% live in low–middle-income countries.” And price is an important consideration even for developed countries, he emphasized.
Diabetes UK has said that the costs of treating diabetes threaten to bankrupt the National Health Service, for example.
There “is a massive difference” in cost for an annual supply of antidiabetic agents, which, in the United States, ranges from $96 US for glipizide and $192 for glyburide — both sulfonylureas — to $1243 for generic metformin to around $5000 for DPP-4 inhibitors and around $5400 for SGLT2 inhibitors, he noted.
A recent study reported that sulfonylureas are still used by 31% of patients with diabetes in the United States, and rates of use are even higher in Europe — 41% to 45% of patients in the United Kingdom and 47% of patients in the Netherlands use a sulfonylurea, he added.
There may however be differences between countries in the type of sulfonylurea that is used, Dr Khunti explained.
“In the UK, gliclazide is the [sulfonylurea] that is used the most,” he said, noting that it does seem to have a better profile than other sulfonylureas in the ADVANCE trial.
And “over time we have improved and use a lower dose” of gliclazide, he said.
Gliclazide is not available in the United States, Dr Rasouli noted, but glimepiride and glipizide are available.

Get Patients on Whatever Therapy They Can Afford

Summarizing, Dr Khunti said: “What I’ve shown you is there are controversial issues in terms of whether we use sulfonylureas or not, and a lot of it comes down to affordability.”
“We have great drugs, but we are not using them in a timely manner, and…we are waiting far too long to intensify therapy in patients.”
“We should be…getting these patients on whatever therapy we can afford, bringing HbA1c down to control from diagnosis, keeping the HbA1c down for as long as possible, as safely as possible, with whatever therapy is available and affordable to the patient.” That is more likely to generate better outcomes for the patients in the longer term, he explained.
“There’s good efficacy and durability. There’s low risk of hypoglycemia with the second-generation sulfonylureas. We’ve established long-term benefit with decreased risk of micro- and to a certain extent macrovascular complications from randomized controlled trials.”
And sulfonylureas are affordable for the 80% of diabetes patients worldwide who reside in low- to middle-income countries, he reiterated.

Dr Khunti reports that he is a speaker and on the advisory panel for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Servier, Eli Lilly, Janssen, and Novo Nordisk. He is also a consultant and speaker for AstraZeneca, Novartis, Sanofi, Merck, Janssen, Boehringer Ingelheim, and Servier, and he is a speaker for and receives research support from AstraZeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Eli Lilly, Boehringer Ingelheim, Merck, and Roche.
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American Diabetes Association 2017 Scientific Sessions; June 9, 2016; San Diego, California. Session 3-CT-MS04



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