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FDA Approves Fast-Acting Mealtime Insulin

A new formulation of Insulin Aspart can offer better glycemic control and may also be given after meals.

Postprandial glucose control is one of the challenging tasks of insulin dosing for patients with type 1 diabetes. Maintaining low glucose levels after meals has shown to slow the progression of diabetes-associated complications. The need for fast-acting insulin becomes evident when a basal bolus cannot control post-prandial glucose levels. Efforts have been made to develop an ultrafast insulin action with improved absorption time into the bloodstream. This can serve as an advantage in allowing the patient to receive the insulin after meals, and still retain optimal post-prandial glucose control. The addition of niacinamide, a derivative of Vitamin B3, offers a new formulation of Aspart insulin known as faster-Aspart (FIAsp). This product can accelerate the insulin onset of action and increase its bioavailability, as compared to regular Aspart (IAsp).

A randomized double-blind trial was conducted to test the efficacy of FIAsp compared with IAsp for 26 weeks in a total 1143 T1D patients. The FIAsp was tested both before and after meals. Both insulin products were given with basal bolus once- or twice-daily Levemir. The study included adults with T1D who had long-term use of insulin and no major cardiovascular comorbidities. Patients were randomized 1:1:1 to receive mealtime FIAsp, IAsp, or open-label postmeal FIAsp while continuing with insulin detemir. Mealtime bolus insulins were injected 0–2 min before a meal; postmeal FIAsp was injected at a fixed time of 20 min. after the start of the meal.

Meal carbohydrate content and pre-prandial plasma glucose (PG) values were used to determine bolus insulin doses for subjects following the principles of flexible dosing. Adjustments were made several times daily by the subject in accordance with the insulin-to-carbohydrate ratio and the PG correction (sensitivity) factor. Bolus titrations were measured to target glucose levels between 71–108 mg/dL for breakfast, lunch, and dinner doses.

Both mealtime and postmeal dosing of FIAsp were found to be noninferior to mealtime IAsp in terms of change from baseline in HbA1C (p<0.0001). The reduction in HbA1C was greater for mealtime FIAsp than for IAsp (P = 0.0003). When post-meal FIAsp was compared with IAsp, the results were not statistically significant. The odds of achieving HbA1C<7.0% were higher with mealtime FIAsp compared with IAsp (odds ratio 1.47, p = 0.0405) and again, not statistically significantly different between postmeal FIAsp and IAsp.

The estimated glucose level reduction from baseline in the 1h and 2h post-prandial  glucose were higher with mealtime FIAsp compared to IAsp. (p=0.0375 at 1h, p<0.001 at 2h post prandial). However, postmeal FIAsp proved to be less effective than IAsp reducing post-prandial glucose after 1 hour, and their difference was not statistically significant after 2 hours. These results proved mealtime FIAsp effective in controlling the post-prandial glucose, but less effective with postmeal FIAsp. The proportions of subjects achieving the 2-h PPG target 140 mg/dL by week 26 were 42.7% with mealtime FIAsp, 39.6% with postmeal FIAsp, and 38.6% with mealtime IAsp.

During the trial, the daily bolus insulin doses increased in all three treatment groups. By the end of the trial, the doses were comparable between FIAsp (mealtime or postmeal) and IAsp, approximately 0.8 U/kg for all three groups. No statistically significant difference was seen in overall rate of severe or confirmed hypoglycemic episodes between FIAsp (mealtime or postmeal) and IAsp. As expected, due to the pharmacokinetics of the faster acting insulin, there was a slight higher rate of hypoglycemia in the first hour after a meal in the mealtime FIAsp when compared to IAsp.

The strengths of this trial include a large pool of participants and the double-blinding of subjects. Additionally, basal insulin dose was optimized on an individual basis prior to randomization with limited adjustments during the trial, which allowed a better evaluation of the effect of the different bolus regimens. However, all subjects received the same 0.1 units/kg body weight bolus, and no adjustment in the individual insulin-to-carbs ratios, therefore, the insulin dose was an approximation of their daily usual dose.

This trial has demonstrated that FIAsp given at mealtimes is noninferior to IAsp in terms of HbA1C reduction while offering superior control of pp-glucose excursions, without increased risk of overall hypoglycemia. Additionally, FIAsp offered the option of dosing up to 20 minutes post-meal while maintaining overall glycemic control and without increased rates of overall hypoglycemia.

Practice Pearls:

  • FIAsp insulin given at mealtime offers lower post-prandial glucose levels when compared to regular Aspart.
  • FIAsp insulin has proven to be a safe and effective lowering HbA1C in patients with type 1 diabetes.
  • The risk of hypoglycemia related to FIAsp is overall not significantly higher when compared to regular Aspart.

References:

David Russel-Jones, Bruce W. Bode.  Fast-Acting Insulin Aspart Improves Glycemic Control in Basal-Bolus Treatment for Type 1 Diabetes: Results of a 26-Week Multicenter, Active-Controlled, Treat-to-Target, Randomized, Parallel-Group Trial (onset 1) Diabetes Care 2017 Jul; 40(7): 943-950

 

Fabio Rodriguez, PharmD. candidate 2018, LECOM School of Pharmacy