Sotagliflozin Added to Insulin in Type 1 Diabetics

Shanterra Grable, Mercer University College of Pharmacy

Type 1 diabetes, previously considered juvenile diabetes, affects approximately 29 million adults worldwide. It develops when the pancreas stops producing insulin, eliminating the body’s ability to maintain glucose control. The autoimmune disease can have a rapid onset and must be managed with insulin administered via injection or by pump.  It is  approximated that less than one-third of people living with type 1 diabetes achieve the target A1c of less than 7%. [1]

Sotagliflozin is the newest agent in a class of antidiabetic agents known as sodium –glucose cotransporter 1 and 2 (SGLT2) inhibitors. Prior phase two studies on sotagliflozin have shown improved glycemic control, reduced body weight, and reduced glycemia in both type 1 and type 2 diabetics. None of the current medications on the market are approved for use in conjunction with insulin to lower glucose in type 1 diabetic patients. The inTandem3 phase three trial evaluated the effects of sotagliflozin when used in combination with insulin on glycemic control, instances of severe hypoglycemia, and diabetic ketoacidosis in adults with type 1 diabetes. [2]

Effects of sotagliflozin added to insulin in patients with type 1 diabetes
Design Randomized, double-blind, phase three placebo controlled trial; N=1,402
Objective To evaluate the safety and efficacy of sotagliflozin in combination with insulin in type one diabetes patients
Study Groups Sotagliflozin 400 mg/day (n=699) or placebo (n=703)
Methods Patients in the sotagliflozin group took two 200 mg tablets before the first meal of the day. Patients in the placebo group also took two tablets before the first meal. All patients continued their previous insulin regimen. The mealtime insulin was reduced by 30% for the first meal after starting the medication. Investigators were allowed to adjust insulin doses to meet the target blood glucose levels based on blood glucose readings .
Inclusion criteria: treatment with insulin at a stable basal dose for at least two weeks prior to screening, A1c of 7.0 to 11.0%, BMI at least 18.5 kg/m2
Exclusion criteria: severe hypoglycemia or diabetic ketoacidosis during previous month, two or more episodes of diabetic ketoacidosis during previous six months, estimated Glomerular Filtration Rate (eGFR) <45 ml/min
Duration October 2015 to April 2017
Primary Outcome Measure Glycated hemoglobin < 7.0% at week 24
Baseline Characteristics Sotagliflozin (n=699) Placebo (n=703)
Age, years 43.3 ± 14.2 42.4 ±14.0
Females- no. (%) 341 (48.8) 364 (51.8)
Race or ethnic group (no. (%)
White 619 (88.6) 621 (88.3)
Black 24 (3.4) 22 (3.1)
Asian 7 (1.0) 5 (0.7)
Hispanic 49 (7.0) 47 (6.7)
Native American or Alaska Native 1 (0.1) 5 (0.7)
Native Hawaiian or other pacific islander 1 (0.1) 0
Other 47 (6.7) 50 (7.1)
Duration of diabetes, years 20.5±12.4 19.6±12.1
Glycated hemoglobin, % 8.26±0.96 8.21±0.92
Fasting plasma glucose, mg/dl 165.1±71.6 163.4±69.1
Weight, kg 82.40±17.13 81.55±17.03
BMI 28.29±5.13 28.10±5.18
BMI ≥25, no. (%) 495 (70.8) 497 (70.7)
Systolic blood pressure, mmHg 122.0±15.3 121.8±14.8
Diastolic blood pressure, mmHg 76.4±8.8 76.7±9.1
Systolic blood pressure ≥130 mmHg, no. (%) 203 (29.0) 203 (28.9)
Daily total dose of insulin, IU/kg 0.69±0.28 0.71±0.29
Insulin dose, IU/day
Total 56.88±27.60 58.35±29.09
Basal 29.54±16.29 29.63±15.54
Bolus and corrections 27.34±16.97 28.72±19.04
Type of insulin therapy, no. (%)
Subcutaneous injections 424 (60.7) 423 (60.2)
Pump 275 (39.3) 280 (39.8)
Results
End point Sotagliflozin (n=699)- no./ total no. (%) Placebo (n=703)- no./ total no. (%) Difference (95% CI) p value
Patients with glycated hemoglobin <7.0% and no severe hypoglycemia or diabetic ketoacidosis
All patients <0.001
Patients that used insulin pump 200/699 (28.6) 107/703 (15.2) 13.4 (9.0 to 17.8) <0.001
Patients that did not use insulin pump 88/275 (32.0) 45/280 (16.1) 15.9 (8.6 to 23.3) <0.001
Patients with glycated hemoglobin ≥7.0% and ≥ one episode of severe hypoglycemia 16/699 (2.3) 13/703 (1.8) 0.4 (-1.0 to 1.9) 0.56
Patients with glycated hemoglobin ≥ 7.0% and ≥ one episode of diabetic ketoacidosis 18/699 (2.6) 4/703 (0.6) 2.0 (0.7 to 3.3) 0.003
Adverse Events Common Adverse Events: diarrhea (4.1% in sotagliflozin and 2.3% in placebo), genital mycotic infection (6.4% in sotagliflozin and 2.1% in placebo), bone fractures (n=4 sotagliflozin and n=5 placebo)
Serious Adverse Events: severe hypoglycemia (3.0% sotagliflozin and 2.4% placebo)
Percentage that Discontinued due to Adverse Events: 6.3% sotagliflozin and 2.3% placebo
Study Author Conclusions In type 1 diabetes patients, the proportion of patients that achieved a glycated hemoglobin <7.0% was higher in the group that received sotagliflozin than placebo. Rates of diabetic ketoacidosis were higher in the sotagliflozin group than placebo.

 

Since the trial was only 24 weeks, more time is needed to determine if the positive results seen with sotagliflozin in conjunction with insulin can be sustained. Investigators were blinded to patient A1c levels prior to the start of the trial. Had investigators received this information, the insulin dosage may have been adjusted to better reach the target A1c; however, adjusting the insulin dosage would not show the full potential of the sotagliflozin to lower glucose. The trial protocol had measures to  limit the instances of diabetic ketoacidosis which could have influenced the study results to show less instances of diabetic ketoacidosis. At the time of the study, no artificial pancreas system had been approved; therefore, there is no information yet available on the use of sotagliflozin in a patient utilizing an artificial pancreas. Sotagliflozin may be a new and effective option for type 1 diabetics achieving tighter glycemic control.

 

References

[1] Type 1 diabetes facts. Juvenile Diabetes Research Foundation website. http://www.jdrf.org/about/what-is-t1d/facts/. Accessed December 14, 2017.

[2] Garg SK, Henry RR, Banks P, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med. 2017; Accessed December 14, 1017.

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s