Low-Dose SGLT2 Inhibitor May Protect Kidneys in Youth With T1D

ORLANDO — Adding a low dose of an SGLT2 inhibitor to insulin improved renal function and glycemic control in adolescents with type 1 diabetes (T1D), the late-breaking ATTEMPT trial found.

In the 98-patient study, treatment with a 5-mg dose of oral dapagliflozin (Farxiga) showed a renal-protective effect versus placebo, leading to a significant attenuation in glomerular filtration rate (GFR), the “gold standard” for measuring kidney function, said Farid Mahmud, MD, of the University of Toronto in Canada.

“These were not estimates of glomerular filtration,” he said during his presentation at the American Diabetes Association (ADA) annual meeting. “These were direct measurements … which are more invasive but they are far more accurate to assess kidney function.”

Furthermore, treatment with the oral SGLT2 inhibitor yielded a significant 0.48% reduction in HbA1c over a 22-week period compared with placebo (P=0.001).

“This does not replace insulin therapy,” Mahmud emphasized, noting that the drug was added to standard insulin therapy.

One of the earliest signs of kidney complications in diabetes is an increase in GFR, referred to as hyperfiltration. And adolescence is typically a time where GFR is elevated due to kidney stress.

It’s important to intervene “early with the potential to slow or ameliorate the rate of kidney decline as these individuals age,” he said, noting that 50% of T1D patients develop chronic kidney disease (CKD) in adulthood.

Several SGLT2 inhibitors, including dapagliflozin, are approved for type 2 diabetes, and the drugs have already been shown to have renal-protective effects in this setting; dapagliflozin and empagliflozin (Jardiance) are also now approved to reduce the risk of CKD progression as well, regardless of diabetes status.

However, no drug in this class is approved for T1D due to safety issues, particularly an increased risk for hypoglycemia and diabetic ketoacidosis (DKA), often when tested at higher doses. While there were no significant differences in adverse events between the two groups in the current study, there was a higher number of elevated blood ketone events in the dapagliflozin group.

“We need to establish safety — that’s number one,” Mahmud said when discussing next steps following the trial. “We have the emergence of technologies that can enhance safety with regards to ketone monitoring.”

Although overall rates of DKA were low, there were 106 events of blood ketone levels 0.6 mmol/L or higher in the dapagliflozin group versus 62 events in placebo (P<0.001). “But we see ketosis in both groups because these individuals have type 1 diabetes,” Mahmud said, highlighting the importance of patient-centered DKA risk mitigation strategies.

Only one case of DKA occurred in the trial, a mild case in the dapagliflozin group. There were no differences in genitourinary tract infections — a known adverse event with this drug class.

The double-blind ATTEMPT (Adolescent Type 1 Diabetes Treatment with SGLT2i for Hyperglycemia and Hyperfiltration) trial randomized 98 adolescents with T1D (for at least 12 months) ranging in age from 12 to 21. Dapagliflozin was taken orally, once-daily. The 5-mg dose was half that of the 10-mg recommended daily dose, according to the label.

At baseline, all participants were on daily insulin injections or pump therapy. The minimum total daily dose of insulin was ≥0.6 units/kg/day. Baseline HbA1c was between 7-10%. Some exclusion criteria were type 2 diabetes, a BMI over the 99.9th percentile, or DKA within 90 days of screening.

“This allows us a really important framework in how we evaluate physiologic, metabolic, and clinically relevant outcomes that are patient-centered when we look at adjunctive therapies in addition to insulin to optimize management in youth with type 1 diabetes,” Mahmud concluded.

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