EASE: Empagliflozin Beneficial in Type 1 Diabetes, DKA a Risk

Miriam E. Tucker

October 11, 2018

BERLIN — The sodium-glucose cotransporter type 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) improved glycemic control and weight in type 1 diabetes, but also increased the risk for diabetic ketoacidosis (DKA), new data show.

Findings from the Empagliflozin as Adjunctive to Insulin Therapy (EASE) program were presented October 4 here at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting and simultaneously published in Diabetes Care

SGLT2 inhibitors are one of the newer classes of oral drugs used to treat type 2 diabetes.

The new data come from two double-blind, placebo-controlled phase 3 trials: EASE-2, with a total of 730 patients with type 1 diabetes and HbA1c 7.5% to 10.0% randomized to 10 mg or 25 mg of empagliflozin daily or placebo for 52 weeks, and EASE-3, with 734 similar patients randomized to 2.5 mg, 10 mg, or 25 mg of empagliflozin or placebo daily for 26 weeks.

Overall, empagliflozin significantly improved glycemic control and weight without increasing hypoglycemia, but the 10-mg and 25-mg doses — the two currently approved for treating type 2 diabetes — were associated with a three- to four-fold increased risk for DKA as well as genital infections.

After the data were presented during the 90-minute session at the EASD meeting, two speakers expressed differing views on the relative benefit–risk calculation for use of empagliflozin, or other SGLT2 inhibitors, in patients with type 1 diabetes.

Study coauthor Lori M. Laffel, MD, chief of the pediatric, adolescent, and young adult section of the Joslin Clinic, Boston, Massachusetts, noted that SGLT2 inhibitors represent an opportunity for meeting unmet needs in type 1 diabetes — in terms of managing both glycemia and weight — and she offered recommendations for mitigating the DKA risk associated with SGLT2 inhibitors.

"There is an opportunity here that we may have a way to optimize benefit, capitalize on the efficacy, while minimizing risk associated with these agents, in a population where there are already inherent risks for acute complications," Laffel said.

However, independent commentator Thomas R. Pieber, MD, of the department of endocrinology and diabetology at the Medical University of Graz, Austria, pointed out that the DKA associated with SGLT2 inhibitor use may be particularly difficult to detect early on, as it often occurs in the setting of euglycemia rather than hyperglycemia. And two other common DKA symptoms — thirst and frequent urination — are also side effects of the drug.

Thus, he noted, "Three of the most important warning signals for DKA are lost."

Pieber, who was the principal investigator for the 4-week EASE-1 trial (Diabetes Technol Ther. 2017;19:49-60) but was not involved in EASE-2 or EASE-3, also faulted the investigators for not investigating a 5-mg dose in these latter studies, and said that further data are "urgently needed" before SGLT2 inhibitors are approved for use in patients with type 1 diabetes.

Multiple Cardiometabolic Benefits

In EASE-2 and EASE-3, mean placebo-corrected HbA1c reduction after 26 weeks of treatment was dose-dependent, by 0.54 percentage points with the 10-mg dose and 0.53 percentage points with the 25-mg dose in EASE-2 and by 0.28 percentage points with the 2.5-mg dose in EASE-3 (all P < .0001).

Greater HbA1c reductions were achieved among the 60% of patients who had baseline levels of 8% or greater (up to 0.64, 0.70, and 0.35 percentage points for the 25-mg, 10-mg, and 2.5-mg doses, respectively; P < .0001).

Empagliflozin also produced significant placebo-corrected body weight reduction after 26 weeks of 3.4 kg (7.5 lb), 3 kg, and 1.8 kg for the 25-mg, 10-mg, and 2.5-mg doses, respectively (all P < .0001).

Systolic blood pressure was reduced with empagliflozin by 3.7 mmHg, 3.9 mmHg, and 2.1 mmHg, respectively, for the 25-mg, 10-mg, and 2.5-mg doses (P < .0001 for 25 mg and 10 mg, P < .05 for 2.5 mg).

Total daily insulin doses were also significantly reduced in all three empagliflozin groups, by 12.6%, 9.5%, and 6.4%, respectively (P < .0001 for all).

Safety Data: Increased DKA, Genital Tract Infections

Over weeks 5 to 26, none of the three empagliflozin doses increased the rate of investigator-reported symptomatic hypoglycemia (< 54 mg/dL) or severe hypoglycemia. Patient-reported hypoglycemic events were reduced with empagliflozin 10 and 25 mg up to 52 weeks.

The DKA risk appeared to be dose-dependent. Although the rate of confirmed adjudicated DKA cases was low in the empagliflozin 2.5-mg dose group and similar to placebo (0.8% and 1.2%, respectively), DKA rates were higher in the empagliflozin 10-mg and 25-mg groups (4.3% and 3.3% for the empagliflozin doses respectively, compared with 1.2% for placebo).

Severe DKA events occurred in one patient in the placebo group, no patients in the 2.5-mg group, two patients with empagliflozin 10 mg, and six patients with empagliflozin 25 mg.

One of those six patients died because of delayed diagnosis and treatment for DKA. Most patients with DKA had at least one precipitating factor, such as concomitant illness/infection or reduced insulin intake.

In the baseline subgroup analyses of the two trials, female sex and insulin pump use were identified as important DKA risk factors in the higher-dose empagliflozin groups. 

Genital infections occurred in 12.8% of patients taking empagliflozin 10 mg, 14.3% of those taking 25 mg, and 4.3% of patients in the placebo group in EASE-2. In EASE-3, the rates were 5.4% with empagliflozin 2.5 mg versus 2.5% with placebo.

Based on all the data, the 2.5-mg dose might represent the "sweet spot" for SGLT2 inhibition in type 1 diabetes, Laffel said.

Can the DKA Risk Be Mitigated?

Laffel pointed to two articles describing strategies for minimizing the risk for DKA in patients with type 1 diabetes, including frequent personalized text messaging (J Diabetes Sci Technol. 2017;11:468-475) and a protocol in which the patient carries a wallet card with the instructions "STop the SGLT2 inhibitor, Inject bolus insulin, Consume 30 grams of carbohydrates, and Hydrate (STICH)" (Diabetes Technol Ther. 2018;20:571-575).

The back of the wallet card contains contact information for the patient's healthcare provider and instructions for emergency personnel.

Laffel also outlined further provider-directed measures for mitigating DKA risk, including education of patients, family members, payers, and other stakeholders about the atypical DKA associated with SGLT2 inhibitor use, reinforcement of sick-day management, avoiding use of SGLT2 inhibitors in patients with disordered eating patterns or low-carbohydrate diets, and using the lowest effective SGLT2 inhibitor dose.

But Pieber advised that several knowledge gaps be filled before SGLT2 inhibitors are approved for use in patients with type 1 diabetes, including biomarkers to identify those at greatest risk, cardiovascular outcome trials to determine whether the cardiovascular benefits seen in type 2 diabetes extend to type 1 diabetes, and mechanistic studies to better understand the risk.

Such mechanistic studies have been requested by both the European Medicines Agency and US Food and Drug Administration since the DKA risk with SGLT2 inhibitors was first identified, he noted, but "they haven't been done yet, unfortunately."

EASE-2 and EASE-3 were supported by Boehringer Ingelheim and Eli Lilly. Laffel has been a consultant for and/or received grant support from Johnson & Johnson, Eli Lilly, Sanofi, Novo Nordisk, MannKind, Merck, Bristol-Myers Squibb, AstraZeneca, Roche, Dexcom, Unomedical-ConvaTec, Insulet, and Boehringer Ingelheim, National Institutes of Health, JDRF, American Diabetes Association, Helmsley Charitable Trust, Dexcom, and Insulet. Pieber has received research support and/or is an advisory board member for Novo Nordisk, AstraZeneca, Adocia, Arecor, and Sanofi. He is also an employee of the Center for Biomarker Research in Medicine.  

Diabetes Care. Published online October 4, 2018. Abstract

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