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SGLT-2i Use in Type 1 Diabetes May Help Maintain Glycemic Levels

Nov 10, 2018
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Arsalan Hashmi, PharmD. Candidate, LECOM College of Pharmacy

Empagliflozin shows improvements in A1C while also having major adverse effects, but there could be a balance.

The results of the Empagliflozin as Adjunctive to Insulin Therapy (EASE) trial were presented at the 2018 annual meeting of the European Association for the Study of Diabetes. The study looked at the introduction of empagliflozin, an SGLT-2 inhibitor for the glycemic control treatment of type 1 diabetes. The majority of people who have type 1 diabetes cannot manage their blood sugars with their insulin regimens, and those who are managing may have obesity. SGLT-2 inhibitors, in theory, may be compatible with type 1 diabetes since they work independent of insulin and excrete the body’s glucose through urine.

This study looked at T1D from two studies: the EASE-2 conducted over 1 year and EASE-3 conducted over 26 weeks. Both were randomized, multicenter, double-blinded trials that looked at once-a-day administration of empagliflozin 10 mg and 25 mg. EASE-2 had 730 participants, while EASE-3 had 977 participants randomized. Patients with recent diabetic ketoacidosis were excluded from the study. For the first six weeks, patients increased their dose of insulin, followed by stable doses for two weeks. Insulin was reduced by 10% if A1C was lower than 8%. The amount of total daily insulin was recorded on a daily basis. Since the development of DKA had been seen in similar studies, patients were told to seek medical attention for a beta hydroxybutyrate level higher then 1.5 mmol/L. Statistical analysis was done by two-sided t test and mixed-effects model for repeated measures.

This study showed many benefits for people with type 1 diabetes who were on empagliflozin. The primary endpoint was a reduction in A1C seen across both studies. The largest A1C reduction was seen in 60% of patients [empagliflozin 10 mg: – 0.70%, 25 mg: -0.64%]. A decrease in both body weight [up to 3.4 kg] and blood pressure was equivalent for both 10 mg and 25 mg empagliflozin. Insulin dosage was decreased up to 13.3% in patients taking 25 mg doses. Patients reported less hypoglycemia on the medication, and nocturnal hypoglycemia decreased by up to 37%.

There are big safety concerns with this drug. Aside from genital infections, there is a dose-dependent risk for diabetic ketoacidosis, a dangerous condition that occurs when the body uses fatty acids for energy instead of glucose. In this case, it most likely occurs due to the reduction of insulin with the introduction of the SGLT-2 inhibitor, since insulin prevents the use of fatty acids as energy. Empagliflozin 10 and 25 mg had higher rates of DKA than placebo at 4.3% and 3.3% respectively. Analysis of the two groups revealed that females and patients on insulin pumps had the highest risk of DKA. Dr. Thomas Peiber MD, who was involved in EASE-1, pointed out that a major problem with implementing empagliflozin into the treatment of T1D is that DKA becomes much more difficult to detect. DKA usually takes place during hyperglycemia, but with this combination therapy and reduction of insulin, DKA will occur at normal blood glucose levels. Secondly, Peiber stated that two of the side effects of SGLT-2 inhibitors are the same as the warning signs for DKA — thirst and frequent urination. He stated that more studies are needed, including biomarkers to detect DKA before adding it as a therapy for T1D.

This study looked at the risk vs benefit of implementing empagliflozin into T1D therapy. Although there are many benefits to one risk, as previously stated it is worth noting that the severity of the DKA increased with the dose of empagliflozin, with the most severe DKA occurring in the group taking 25 mg. The smallest dose of 2.5 mg over the 26-week period showed a reduced risk of DKA compared to placebo at 0.8% to 1.2% respectively. Along with this lower risk, it also demonstrated, to a lesser extent, the same effect on A1C, body weight, and blood pressure. Because of this, this study suggests that lower doses of SGLT-2 inhibitors should be used in T1D under certain conditions. DKA risk was correlated with a drop in injected insulin, thus further studies should be done with low dose empagliflozin to find the lowest level of insulin that patients with type 1 who are taking SGLT-2’s can go. SGLT-2 inhibitors should be avoided in a low carb diet, as well as alcohol abuse.

Further studies are currently under way on the renal and cardiovascular benefits of the drug in people who have type 1 and type 2 diabetes.

Practice Pearls:

  • Although there were many benefits seen with the addition of empagliflozin, including A1C reduction and weight loss, there was a dose-dependent relationship with developing diabetic ketoacidosis.
  • SGLT-2 inhibitors hide the signs of DKA, namely frequent urination and thirst. Detection is also more difficult since the DKA occurs at normal glucose levels.
  • A low 2.5 mg dose showed to be a protective factor for DKA over placebo and still had the benefits of higher doses. Studies of the 2.5 mg dose should be conducted.

References:

EASE: Empagliflozin Beneficial in Type 1 Diabetes, DKA a Risk – Medscape – Oct 11, 2018.

Rosenstock, Julio, et al. “Empagliflozin as Adjunctive to Insulin Therapy in Type 1 Diabetes: The EASE Trials.” Diabetes Care, American Diabetes Association, 3 Oct. 2018, doi.org/10.2337/dc18-1749.

Arsalan Hashmi, Pharm. D. Candidate 2019, LECOM School of Pharmacy