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People with type 2 diabetes treated with metformin plus a sulfonylurea with high affinity for cardiac mitochondrial adenosine triphosphate–sensitive potassium (mitoKATP) channels, such as glyburide and glipizide, had a significant, adjusted 18% higher relative rate of major adverse cardiovascular events (MACE) compared with matched patients who received a low-affinity sulfonylurea, such as glimepiride, in an observational study of more than 50,000 matched pairs of patients in Taiwan.

The increased MACE risk primarily was associated with hospitalization for myocardial infarction, can you take naproxen and motrin together and the risk was greatest during the first 90 days of treatment and with a high dose of a sulfonylurea with high mitoKATP channel affinity, write Meng-Ting Wang, PhD, and associates in a report recently published in JAMA Network Open.

These findings suggest that “the high-affinity blockage of cardiac mitoKATP channels may act as an important determinant of sulfonylurea-related adverse cardiovascular events in patients with type 2 diabetes,” conclude the authors, who are affiliated with several institutions in Taipei, Taiwan.

The findings both confirm and refine a long-standing suspicion that at least some agents in the sulfonylurea class may increase risk for cardiovascular disease events, although evidence for this adverse effect is largely considered inconclusive.

In part because of safety concerns like this ― as well as other relative shortcomings of sulfonylureas, such as weight gain and relatively higher rates of hypoglycemia — the drug class has dropped from secondary to tertiary agents in the hierarchy of antidiabetic drugs in some sets of treatment recommendations. Despite this, sulfonlyurea use persists, especially in lower-income countries but also in the United States, owing to the affordability of agents in this class.

For example, glimepiride sells at many US pharmacies for as little as $20 for as much as a 6-month supply, less than 1% of the full retail cost of many agents now favored for treating patients with type 2 diabetes, such as the sodium-glucose cotransporter 2 (SGLT2) inhibitors and the glucagon-like peptide-1 (GLP-1) agonists.

De-emphasizing Sulfonylureas

“This study is part of an ongoing series of observations suggesting some of the challenges of sulfonylureas in the management of diabetes,” commented Robert A. Gabbay, MD, PhD, chief scientific and medical officer for the American Diabetes Association (ADA).

The findings “suggest there may even be differences between specific sulfonylurea analogs,” Gabbay said in an interview. He also highlighted that the ADA’s annual Standards of Care in Diabetes―2023 management recommendations, as well as in recent prior editions, “de-emphasize” use of sulfonylureas “in favor of others that show cardiovascular benefits,” such as metformin, the SGLT2 inhibitors, and the GLP-1 agonists.

“Currently, two opposing opinions are present in the literature. Some people consider that there is almost no more place for sulfonylureas when taking into account alternative new medications that showed advantages compared with older agents,” wrote André J. Scheen, MD, PhD, in an assessment of sulfonylureas published in 2021.

“Others make a plea for maintaining a right place of sulfonylureas in the therapeutic armamentarium of type 2 diabetes, especially in countries with limited resources,” noted Scheen, professor and head of the Division of Diabetes, Nutrition, and Metabolic Disorders at the Academic Hospital of Liège, Belgium.

Low-Affinity Sulfonylureas Predominate in Taiwan

The new JAMA Network Open study used data from more than 670,000 people in the Taiwan Diabetes Mellitus Health Database from 2006–2017, which included essentially all people in Taiwan who were newly diagnosed with diabetes during that period. This cohort included more than 280,000 adults who received sulfonylurea as second-line treatment after metformin; nearly 248,000 of these people qualified for the analysis, mostly because at least 1 year of data were available for them.

The study cohort included about 193,000 on a low-affinity sulfonylurea, glimepiride, or gliclazide (the latter is not approved for US marketing) and 54,411 on a high-affinity sulfonylurea, glyburide, or glipizide. These four agents constitute more than 99% of the sulfonylureas prescribed for use with metformin for these Taiwanese adults during the study period.

These numbers indicate that in Taiwan during the 12 years studied, more than three quarters of people with diabetes who received a sulfonylurea added on top of metformin were on a low-affinity sulfonylurea associated with a lower risk for MACE.

The main analysis focused on 53,714 matched pairs of people from this study set, with one member of the pair on a low-affinity agent matched with someone on a high-affinity agent. The analysis also adjusted for demographic and clinical characteristics to further reduce the possible influence of confounding not resolved by matching.

The primary endpoint of MACE included cardiovascular death, hospitalization for myocardial infarction, and hospitalization for ischemic stroke during an average follow-up of about 10 or 14 months, depending on treatment subgroup.

The analysis showed that treatment with a high-affinity sulfonylurea was significantly linked with an 18% higher rate of MACE compared with those treated with a low-affinity sulfonylurea. This was primarily driven by a significant 34% relative increase in the rate of myocardial infarction among those who received a high-affinity agent. All-cause death in the high-affinity subgroup was a significant 27% higher among those who were taking a high-affinity agent compared with those taking a low-affinity agent. Plus, the rate of severe hypoglycemia was a significant 82% greater with high-affinity sulfonylureas compared with low-affinity agents.

The same team of researchers had previously reported largely similar findings in 2022 in Diabetes Care based on fewer people with type 2 diabetes in Taiwan, using close to 34,000 matched pairs of patients.

The study received no commercial funding. None of the authors have disclosed any relevant financial relationships. disclosures. Gabbay has been an advisor to Lark, Health Reveal, Sweetch, StartUp Health, Vida Health, and Onduo. Scheen has received fees as a lecturer, advisor, or researcher from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, and Servier.

JAMA Netw Open. Published online December 9, 2022. Full text

Mitchel L. Zoler is a reporter with Medscape and MDedge based in the Philadelphia region. @mitchelzoler.

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