Low-carbohydrate diets may underlie some cases of "euglycemic diabetic ketoacidosis" (DKA) associated with use of a newer class of type 2 diabetes drugs, the sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors, the latest research suggests.
Findings from the small randomized trial were published online in Diabetes, Obesity, and Metabolism by Daisuke Yabe, MD, PhD, of the department of diabetes, endocrinology, and nutrition at Kyoto University Graduate School of Medicine, Japan, and colleagues.
"While benefits of SGLT2 inhibitors have been confirmed in various clinical trials, we're facing several concerns on adverse effects of this drug class in clinical settings," Dr Yabe told Medscape Medical News.
Prior case reports of SGLT2-inhibitor–associated DKA among patients with both type 1 and type 2 diabetes — including some with normal or only slightly elevated glucose levels — prompted a warning from the US Food and Drug Administration in 2015 and an alert from the European Medicines Agency early in 2016. (SGLT2 inhibitors are not approved for use in type 1 diabetes but have been used off-label.)
Some of the case reports have been in patients who were either fasting or following strict low-carbohydrate diets, but the current randomized trial of 24 Japanese type 2 diabetes patients is the first to formally demonstrate that SGLT2 inhibitors can enhance ketone production under low carbohydrate conditions, said Dr Yabe.
"Since carbohydrate restriction has been widely used to reduce body weight, doctors should question whether patients are on carbohydrate restriction or not, and if so they need to consult dietitians….Doctors should also mention a possible association of strict carbohydrate restriction with SGLT2-inhibitor–related euglycemic DKA to patients who initiate and continue SGLT2-inhibitor treatment," he advises.
Increasing Risk With Lower Carb Consumption
The multicenter, randomized, open-label, three-arm parallel study involved 24 adult Japanese patients with type 2 diabetes taking either a single oral hypoglycemic agent or a glucagonlike peptide-1 (GLP-1) receptor agonist. All had HbA1c of 10% or lower with one drug or 7% to 10% with no drug treatment, and body mass index of 20 to 30 kg/m2.
They were randomized to one of three diet groups for 14 days, all containing 1800 kcal/day: high carbohydrate/high glycemic index, consisting of 55% total energy from carbohydrates primarily derived from white rice; high carbohydrate/low glycemic index (55% carbohydrate/primarily brown rice); and low carbohydrate/high glycemic index (40% carbohydrate/white rice).
Subjects took 2.5 mg of the SGLT2 inhibitor luseogliflozin (Taisho Pharmaceutical) once daily before breakfast for the final 7 days. Blood samples were taken on days 1, 8, and 15. Continuous glucose monitoring (CGM) was performed twice, on days 5 through 8 and 12 through 15.
Luseogliflozin significantly decreased glucose area under the curve and mean CGM data similarly in all three groups. Fasting plasma glucose, insulin, and glucagon were similar at all time points.
Ketone body production increased in all patients after initiation of luseogliflozin. Although ketone bodies on days 1 and 8 did not differ among the three groups, by day 15 ketones were significantly increased in the low-carb/high-glycemic-index group compared with the other two groups (752 μmol/L vs 502.9 μmol/L for high carb/high glycemic index and 360.9 μmol/L for high-carb/low glycemic index).
Likely to Be a Class Effect
Dr Yabe and colleagues note that the SGLT2-inhibitor class lowers plasma glucose and circulating insulin levels via urinary glucose excretion. The agents also enhance glucagon secretion.
Reduced insulin and elevated glucagon stimulate lipolysis in fat and hepatic ketogenesis, which could trigger onset of euglycemic DKA in people with insulin-dependent type 1 diabetes and also in type 2 diabetes characterized primarily by beta-cell dysfunction, which is more prominent among East Asian populations, including the Japanese.
Luseogliflozin isn't sold in the United States, but Dr Yabe said that there have been case reports of euglycemic DKA among Japanese patients taking various SGLT2-inhibitor agents.
So, he added, "We assume that some of the euglycemic DKA cases in type 2 diabetes reported in the US are also caused by combination of SGLT2 inhibitor and strict carbohydrate restriction."
The trial was funded by Taisho Toyama Pharmaceutical. Dr Yabe received consulting and/or speaker fees from MSD, Novo Nordisk Pharma, Takeda Pharmaceutical, and Taisho Toyama. He also received clinical commissioned/joint research grants from Nippon Boehringer Ingelheim, Eli Lilly, Taisho Toyama Pharmaceutical, MSD, Ono Pharmaceutical, Novo Nordisk, Arklay, and Takeda Pharmaceutical. Disclosures for the coauthors are listed in the paper.
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Diabetes Obes Metab. Published online December 19, 2016. Abstract
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Cite this: Do Low-Carb Diets Cause Diabetic Ketoacidosis With SGLT2 Inhibitors? - Medscape - Jan 25, 2017.
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