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Use of SGLT-2 inhibitors As Adjunct to Insulin In People with Type 1 Diabetes

Apart from Sotagliflozin’s use in the treatment of  people with type 2, SGLT-1 and SGLT-2 inhibitors effects on type 1 currently being explored.

For many years, SGLT-1 and SGLT-2 inhibitors have been widely used among people with type 2 diabetes. Both inhibitors work on the sodium-glucose cotransporter where SGLT-1 inhibitors primarily transport glucose and galactose in the gastrointestinal tract, and SGLT-2 inhibitors aide with renal glucose reabsorption. SGLT-1 inhibitors furthermore help improve postprandial glucose levels, as well as, release GI peptides like GLP-1 to aide with appetite suppression. SGLT-2 inhibitors help reduce hemoglobin A1c levels, lower body weight and blood pressure. Moreover, little hypoglycemic effects are seen with SGLT-2 inhibitors. The use of these inhibitors in people with type 2 diabetes helps maintain glycemic control while preventing weight gain and now studies using SGLT inhibitors in the treatment of people with type 1 diabetes, in conjunction to insulin therapy, shows some promising results in glycemic control.

In a recent study, titled Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes, researchers hypothesized that given the history of SGLT inhibitors on people with type 2, administering these inhibitors to type 1 patients will help to improve glycemic control, as well as facilitate the use of insulin without weight gain. They predicted that the use of SGLT inhibitors, especially SGLT-1 inhibitors will lower postprandial glucose levels in addition to reducing insulin bolus dose thus decreasing risks of hypoglycemia.

The randomized, multicenter, placebo-controlled, double-blind study focused on testing the effects of sotagliflozin in adult patients with type 1. The study included 36 patients where 3 patients were placed in the open-label pioneer group and the remaining 33 patients were placed in the randomized, placebo-controlled, double-blind group. The participants were required to remain on insulin therapy via multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII) via pumps. Patients using either MDI or CSII were then enrolled in the placebo-controlled group. The individuals were randomly placed in a 1:1 double-blind fashion where one group received a daily dose of 400mg sotagliflozin and the other a placebo. Both study drugs were taken 15 minutes prior to having breakfast. Baseline insulin levels were recorded during the initial 7 days, in an inpatient setting. On the first day of the study, one treatment dose was given prior to a mixed-meal tolerance test (MMTT) and before breakfast; no bolus insulin was given. Short-acting insulin dosage was adjusted at each meal.

On the second day of the study, the patients were discharged and instructed to resume their regular daily routines. An Enlite subcutaneous glucose sensor was used to obtain a blinded continuous glucose monitoring (CGM) data on each patient throughout the study.

The primary outcome of the study included treatment effect of total daily bolus insulin from baseline throughout the outpatient setting. One of the secondary outcomes included changes in insulin regimen including daily bolus insulin given with each meal and total daily basal insulin.

Another secondary outcome involved glycemic control when assessing the effects of sotagliflozin treatment during fasting state and after MMTT was administered. Effects of sotagliflozin treatment included treatment on hemoglobin A1c and changes in GLP-1. The intent to treat group included all randomized patients in the placebo-control group.

Results indicated that changes from baseline in total daily insulin use was -32% in the sotagliflozin treatment group and -6.4% for the placebo group. Reductions in bolus insulin from baseline were recorded at different times of the day for both study groups. At breakfast, results among the sotafliglozin treatment group and placebo group were -28.4% vs, 13.6% (P=0.046), respectively. At lunch, results were -25.9% for the treatment group and 7.1% for the placebo group (P=0.08). Finally, results at dinner showed -23.8% for the treatment group and 39.3% for the placebo (P=0.052). Among patients using MDI or CSII, the effects of sotagliflozin on bolus insulin regimens were similar. Furthermore, the use of basal insulin between both groups was similar with a minor decrease from baseline of 2.4% for the sotagliflozin group and 0.2% in the placebo group (P=0.53). In addition, the use of sotagliflozin lowered the mean daily glucose in the outpatient setting; 148.8mg/dL in the treatment group and 170.3 mg/dLfor the placebo group (P=0.010). Sotagliflozin treatment also produced promising results on glycemic control pos-prandially: -16.7mg/dL vs. -4.2mg/dL, at breakfast for the treatment and placebo group, respectively (P=0.034). Hemoglobin A1c also decreased significantly by 0.55% after 29 days of treatment.

There were some adverse events reported in the study, however, none significant enough to discontinue the study. In addition, two cases of diabetic ketoacidosis were reported in patients using the insulin pump, treated with sotagliflozin. According to researchers, the two cases of diabetic ketoacidosis were primarily related to the use of the insulin pump and not to the sotagliflozin.

The authors conclude that the use of 400mg sotagliflozin reduced bolus insulin dose while improving glycemic control among type 1 patients. In addition, sotagliflozin produced a significant decrease in post-prandial glucose levels during the 3-h plasma glucose. Moreover, patients treated with the study drug showed weight loss and decreased systolic blood pressure. These results suggest that the use of sotagliflozin in reducing bolus insulin use can help lower the risk for postprandial hypoglycemia. By using SGLT inhibitors in people with type 1 diabetes, the challenge of using insulin therapy alone for management becomes decreased.

Practice Pearls:

  • SGLT inhibitors are currently being used off-label for the treatment of people who have type 1 diabetes.
  • SGLT-1 inhibitors work by inhibiting that transport of glucose and galactose in the GI tract whereas SGLT-2 inhibitors inhibit glucose reabsorption in the kidneys.
  • SGLT inhibitors reduce post-prandial hypoglycemia, reduce the for bolus insulin dose, and reduce weight gain in people with type 1 diabetes.

References:

Sands, Arthur T., Brian P. Zambrowicz, Julio Rosenstock, Pablo Lapuerta, Bruce W. Bode, Satish K. Garg, John B. Buse, Phillip Banks, Rubina Heptulla, Marc Rendell, William T. Cefalu, and Paul Strumph. “Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes.” Diabetes Care 38.7 (2015): 1181-188. Web. 5 July 2017.

 

Nuha Awad, Doctor of Pharmacy Candidate: Class of 2018; ACCP FSHP