Rapid Insulin Gets Faster in Era of New Technology

MD Magazine CardiologyNovember 2017
Volume 7
Issue 7

A new formulation of insulin aspart (IAsp) with faster onset than the “rapid-acting” version was approved by the FDA on September 29. Fiasp (Novo Nordisk) can be dosed just before a meal and should provide a more natural insulin response with “artificial pancreas” systems and other sensor-augmented continuous subcutaneous insulin infusion (CSII) pumps.

Bruce Bode, MD, president of Atlanta Diabetes Associates and associate professor, Emory University School of Medicine, Atlanta, Georgia, described the development of the faster IAsp when the approval was announced.1

“With Fiasp, we’ve built on the insulin aspart molecule to create a new treatment option to help patients meet their post-meal blood sugar target,” Bode said. “The intention of rapid-acting insulin therapy is to mimic, as much as possible, the natural physiological insulin response that occurs after meals, a process that is important for optimal glycated hemoglobin management.”

The Fiasp formulation includes the adjuvants of niacinamide to hasten absorption from the subcutaneous site and L-arginine to stabilize the molecule. Niacinamide facilitates the breakdown of the insulin hexamer structure, the form secreted from the pancreatic beta cell, into the monomers that form in the blood but are delayed in the subcutaneous environment.

In 1 pharmacokinetic study,2 Fiasp demonstrated a 4.9-minute onset of action, compared with 11.2 minutes with insulin IAsp, and attained half maximal effective concentration in 20.7 minutes, compared with 31.6 minutes with IAsp. The largest effect on blood glucose occurred within the first 15 minutes, when Fiasp produced an area under the curve, the measure of drug amount absorbed into the blood over time, that was 4.5 times that of IAsp.

Although Fiasp and IAsp insulins demonstrate comparable potency, with similar total and maximum lowering of serum glucose, Fiasp produces a greater glucose-lowering effect within 90 minutes after dosing. Both of these insulin analogs provide a more rapid-acting and shorter-duration profile than does human regular insulin and so provide relative protection against the dangerous nocturnal hypoglycemia that has followed dosing of regular insulin with the evening meal.

Chantal Mathieu, PhD, professor of medicine and director of biomedical sciences, University of Leuven, Belgium, and colleagues recently reviewed the relative advantages of the faster insulin analog, acknowledging that some observers are “underwhelmed” by the gain of just a few minutes in onset.3

“However, in our opinion, in real-life settings, these few minutes make a considerable difference to the lives of people with type 1 diabetes mellitus [T1DM],” Mathieu and colleagues expressed.

They pointed out that a gain of a few minutes in onset of insulin improves coverage of meal-induced spikes in blood glucose and enables more convenient dosing shortly before a meal, rather than at some earlier time estimated to accommodate a slower absorption and onset.

“The group in which this difference of a couple of minutes is even more crucial is users of CSII, in particular those who use sensor-augmented pumps,” Mathieu and colleagues indicated. They explained that while the pumps are becoming increasingly sophisticated, they are only as functionally accurate as the rapidity of onset and offset of the insulin.


In a review of the current Endocrine Society Guidelines of Insulin Pump Therapy and Continuous Glucose Monitor Management of Diabetes, Alfonso Galderisi, MD, a postdoctoral associate in the Division of Pediatric Endocrinology and Diabetes, Yale School of Medicine, New Haven, Connecticut, and colleagues described recent advances in diabetes technology systems and encouraged use of the guidelines to apply these developments “during the era of new technology.” 4

“Technology has transformed the way we live, and its effect on our daily life has been increasing exponentially,” Galderisi and colleagues observed. “Isolating diabetes management from technology in this era is an unrealistic and shortsighted expectation.”

The most prominent recent development is arguably the first FDA-approved automated insulin delivery device, which responds in a “closed loop” to glucose levels in interstitial fluid detected by a subcutaneous implanted sensor. The MiniMed 670G (Medtronic) system, which has been described as an artificial pancreas, was approved by the FDA in September 2016 and entered the US market this past June. Other artificial pancreas and sensor-augmented CSII projects are in various stages of development.

The FDA approval was announced by Jeffrey Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health.5 “This first-of-its-kind technology can provide people with type 1 diabetes greater freedom to live their lives without having to consistently and manually monitor baseline glucose levels and administer insulin,” Shuren said.

Galderisi and colleagues characterize the Medtronic system as “a game changer in diabetes treatment [that] opened new avenues to improve diabetes care.” The pivotal study submitted to the FDA demonstrated that the amount of time that blood glucose concentrations were within target range increased by 5% to 6% from baseline through a reduction in both time in hyperglycemia and in hypoglycemia.

On September 27, the FDA approved the FreeStyle Libre (Abbott), described by the manufacturer as a “flash glucose monitoring system” that provides the user with measurements of continuous glucose monitoring without the necessity of calibration from finger stick blood sampling. The device transmits the glucose level measure from the implanted sensor to a mobile reader that users wave over it.

Donald St. Pierre, deputy director of new product evaluation at the Center for Devices and Radiological Health, announced this approval.6 “This system allows people with diabetes to avoid the additional step of finger stick calibration, which can sometimes be painful, but still provides necessary information for treating their diabetes—with a wave of the mobile reader,” he said.

A planned collaboration to link the FreeStyle Libre continuous glucose monitor with an insulin delivery system was announced on July 13 by Abbott and Bigfoot Biomedical.7 In the announcement, Jeffrey Brewer, president and CEO of Bigfoot Biomedical, Milpitas, California, described the investigational delivery systems that use smartphone technology and machine learning automation to adjust insulin delivery. The companies indicated plans to initiate a pivotal trial of the combined systems in 2018.

Another collaboration was announced in July by Roche, Senseonics, and TypeZero Technologies.8 The Senseonics Eversense continuous glucose monitoring system will be paired with the Roche Accu-Check Insight insulin pump and the TypeZero inControl interface software. The companies indicate plans to test the system at 3 sites in Europe.

TypeZero also indicated that it could contribute software to a sensor-augmented CSII project that was approved by the FDA in August9 that combines the touch screen insulin pump technology from Tandem Diabetes Care with the continuous glucose monitor from Dexcom.


Galderisi and colleagues reviewed the studies supporting the FDA approvals of these systems and found evidence that the new technology enables tighter glycemic control, which they anticipate will promote better metabolic control and reduce the long-term complications of diabetes.

“The findings from these studies have been remarkably consistent, demonstrating a significant reduction in hypoglycemia and an increase in time spent within target blood glucose range with the artificial pancreas use as compared to standard of care treatment,” Galderisi and colleagues indicated.

Others, however, have questioned whether there is an association between the use of insulin pumps and short-term diabetes complications, particularly in heightening risk for ketoacidosis in pediatric patients. A recently published, population-based cohort study addressed the question by comparing the occurrence of hypoglycemia, ketoacidosis, and glycemic control with insulin pump or injection therapy in over 30,000 patients with T1DM ranging from children to young adults.10

Beate Karges, MD, of the Division of Endocrinology and Diabetes, RWTH Aachen University Hospital, Germany, and colleagues reported that event rates for severe hypoglycemia were significantly lower with pump therapy compared with injection therapy (9.55 vs 13.97 per 100 patient years). The differences between therapies were statistically significant for all age groups except in children aged 1.5 to 5 years.

In the matched cohort, a total of 842 events of diabetic ketoacidosis occurred in 719 patients. Pump therapy was again associated with significantly fewer events than injections (3.64 vs 4.26 per 100 patient years). The age-group analysis showed the difference to be statistically significant in adolescents and young adults aged 16 to 19 years but not in other age groups.

“The more common use of rapid-acting insulin analogs with pump therapy in this and other studies allows for more flexible therapy with lower glycemic variability, leading to lower rates of acute and long-term diabetes complications, including severe hypoglycemia,” Karges and colleagues reported.

The investigators noted that pump therapy is evolving toward closed-loop and semi-independent, sensor-augmented systems and indicated that their findings have implications for these developments in treating patients with T1DM.

“Results of this study provide further evidence that insulin pump therapy, which is a core element of artificial beta-cell technology, is safe and effective, even in routine diabetes care for unselected patients at a population-based level,” Karges and colleagues concluded.


1. Novo Nordisk receives FDA approval for


, a new fast-acting mealtime insulin [news release]. Plainsboro, NJ: Novo Nordisk; September 29, 2017. http://press.novonordisk-us.com/2017-09-29-Novo-Nordisk- Receives-FDA-Approval-for-


-R-a-New-Fast-Acting-Mealtime-Insulin. Accessed October 4, 2017.

2. Heise T, Hövelmann U, Brøndsted L, Adrian CL, Nosek L, Haahr H. Faster-acting


: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin


. Diabetes Obes Metab. 2015;17(7):682-688. doi: 10.1111/dom.12468.

3. Mathieu C, Gillard P, Benhalima K.


in type 1 diabetes mellitus: getting better all the time. Nat Rev Endocrinol. 2017;13(7):385- 399. doi: 10.1038/nrendo.2017.39.

4. Galderisi A, Schlissel E, Cengiz E. Keeping up with the diabetes technology: 2016 Endocrine SocietyGuidelines of Insulin Pump Therapy and Continuous Glucose Monitor Management of Diabetes. Curr Diab Rep. 2017; 17(11):111. doi: 10.1007/s11892-017-0944-6.

5. FDA approves first automated insulin delivery device for type 1 diabetes [news release]. Silver Spring, MD: US Food and Drug Administration; September 28, 2016. www.fda.gov/newsevents/newsroom/ pressannouncements/ucm522974.htm. Accessed October 4, 2017.

6. FDA approves first continuous glucose monitoring system for adults not requiring blood sample calibration [news release]. Silver Spring, MD: US Food and Drug Administration; September 27, 2017. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm577890.htm. Accessed October 9, 2017.

7. Abbott and Bigfoot Biomedical announce collaboration to develop breakthrough diabetes technologies [news release]. Abbott Park, IL, and Milpitas, CA: Abbott; July 13, 2017. http://abbott.mediaroom.com/2017- 07-13-Abbott-and-Bigfoot-Biomedical-Announce-Collaboration-to-Develop- Breakthrough-Diabetes-Technologies. Accessed October 9, 2017.

8. Senseonics leads development efforts of a long-term “artificial pancreas” system for use in the International Diabetes Closed Loop Trial [news release]. Germantown, MD: Senseonics; July 24, 2017. www.senseonics. com/investor-relations/news-releases/2017/07-24-2017-213021126. Accessed October 11, 2017.

9. Tandem Diabetes Care announces FDA approval and



X2 insulin pump with Dexcom G5 Mobile CGM integration [news release]. San Diego, CA: Tandem Diabetes Care; August 28, 2017. www.businesswire. com/news/home/20170828005281/en/Tandem-Diabetes-Care- Announces-FDA-Approval-Launch. Accessed October 9, 2017.

10. Karges B, Schwandt A, Heidtmann B, et al. Association of insulin pump therapy vs insulin injection therapy with severe hypoglycemia, ketoacidosis, and glycemic control among children, adolescents, and young adults with type 1 diabetes. JAMA. 2017;318(14):1358-1366. doi:10.1001/jama.2017.13994.

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