Abrahamson: For T2DM, Sulfonylureas Still Useful Second-Line Therapy With Metformin

It’s too soon to write an epitaph for sulfonylureas as a second-line therapy with metformin, given the large number of patients with type 2 diabetes mellitus (T2DM) who can benefit from them, according to Martin J. Abrahamson, MD, FACP, medical director at the Joslin Clinic and associate professor of medicine, Harvard Medical School.

The arrival of incretins, coupled with a 2012 report that sulfonylureas caused more cardiac issues than metformin in a large study of veterans,¹ has generated debate over the future of sulfonylureas, which lower blood glucose by increasing the secretion of insulin from pancreatic β-cells.²

In his presentation at the 73rd Scientific Sessions of the American Diabetes Association in Chicago (June 21-25), Abrahamson said there is consensus that metformin is the first-line therapy of choice. But for those patients who cannot achieve therapeutic goals quickly—and Abrahamson said it is key that they do so—sulfonylureas should remain a second- line option for many patients, except those who are at risk for hypoglycemia.

It is especially urgent, he said, to bring blood sugar (A1C) levels below 7%. Diabetes is a progressive disease, and studies show that the closer the newly diagnosed patient is to therapeutic goals for A1C, blood pressure, and low-density lipoprotein (LDL), the easier it will be for the patient to reach those goals.³ Thus, when a single agent does not work, Abrahamson said, “Combination therapy is going to be needed early on if the patients are going to achieve therapeutic goals.” And while there is agreement that metformin should be tried first, “There is no consensus on what to add next.”

Abrahamson reviewed recent studies to evaluate sulfonylureas and alternatives alongside metformin based on their effectiveness, tolerability, cardiovascular effects, durability, and cost. He compared sulfonylureas with thiazolidinediones (TZDs), dipeptidyl peptidase inhibitors (DDP-IVs), glucagon-like peptide receptor (GLP-1) agonists, and insulin. He excluded sodium glucose co-transporter 2 inhibitors because they were too new to the market. (The US Food and Drug Administration granted approval on March 29, 2013.⁴)

While acknowledging the debate, Abrahamson said that for now it makes no sense to abandon sulfonylureas as a second-line therapy, given how they compare with alternatives, using today’s yardsticks. As long as factors like effectiveness, side effects, and cost are what doctors have to go by, they are the criteria that must be used. “Unfortunately, these are the parameters that we have to focus on, because phenotypic and genotypic approaches to determine the most effective therapy are still lacking,” Abrahamson said. A decade from now, that may not be true, he said.

Among the concerns about sulfonylureas is the suspicion that longterm use contributes to a decline of β-cell function, or “burnout.” A study published in November 2012 in Diabetes Technology & Therapeutics found an association between extended sulfonylurea use and deteriorating β-cell function, but not a causal link.⁵ In his review, Abrahamson noted this lack of proof, saying of sulfonylureas, “There is no clear evidence that they hasten the demise of the β-cell.”

Two key advantages of sulfonylureas, based on Abrahamson’s presentation, are their low cost and the limited need for monitoring, compared with alternatives. With the economic cost of diabetes reaching $245 billion a year in the United States,⁶ including $18 billion for glucoselowering medications, price is necessarily a consideration for both doctor and patient, Abrahamson said.

Some 26 million Americans have diabetes,⁶ and 80% are treated by their primary care physicians, Abrahamson said, making simplicity of monitoring essential. Notably, he said, in many cases “submaximal” doses of sulfonylureas have been shown to be as effective as maximal doses.⁷ Still, Abrahamson said, “We need more data,” and “It’s coming.” In June, the National Institutes of Health launched GRADE (Glycemia Reduction Approaches in Diabetes), a comparative effectiveness study that will randomize 5000 patients taking metformin and 1 of the following: sitagliptan (Januvia), a DPP-IV inhibitor; glimepiride (Amaryl), a long-acting sulfonylurea; liraglutide (Victoza), a GLP-1 agonist; and glargine (Lantus), a long-acting insulin analogue.⁸

For now, he cautioned, “Which sulfonylurea you choose, and what dose you use does matter.”

1. Roumie CL, Hung AM, Greevy RA, et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular effects in type 2 diabetes mellitus: a cohort study. Ann Intern Med. 2012:157(9):601-610.

2. National Library of Medicine. Drug record: second generation sulfonylureas. National Institutes of Health website. http://livertox.nih.gov/SecondGenerationSulfonylureas.htm. Accessed Aug 24, 2013.

3. Esposito K, Chiodini P, Bellastella G, Maiorino MI, Guigliano D. Proportion of patients at HbA1c target <7% with eight classes of antidiabetic drugs in type 2 diabetes: systematic review of 218 randomized controlled trials with 78,945 patients. Diabetes Obes Metab. 2012;14(3):228-233.

4. US Food & Drug Administration website. Approval for canagliflozin (Invokana) March 29, 2013. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search. Label_ApprovalHistory#apphist. Accessed August 27, 2013.

5. Shin M, Yu JH, Jung CH et al. The duration of sulfonylurea treatment is associated with β-cell dysfunction in patients with type 2 diabetes mellitus. Diabetes Technol Ther. 2012;14(11):1033-1042.

6. American Diabetes Association, Scientific Statement. Economic Costs of Diabetes in the US in 2012 [published online March 6, 2013]. Diabetes Care. http://care.diabetesjournals.org/content/early/2013/03/05/dc12-2625.full.pdf+html. Accessed August 27, 2013.

7. Hirst JA, Farmer AJ, Dyar A, Lung TW, Stevens RJ. Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis. Diabetologia. 2013;56(5):973-984.

8. National Institutes of Health. NIH begins recruitment for long-term study of diabetes drug efficacy. Press release, June 3, 2013. http://www.nih.gov/news/health/jun2013/niddk-03.htm. Accessed August 27, 2013.

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