Medtronic is looking to address the potentially dangerous issue of hypoglycemia by conducting a study of the low glucose suspend (LGS) feature of the MiniMed Paradigm insulin pump system in people with type 1 diabetes with the hope it can release this product in the U.S. in the next few years.

By: John Parkinson, Clinical Content Coordinator,

Diabetes technology has played a major role in improving the quality of life for people with type 1 diabetes. With insulin pump therapy and continuous glucose monitoring, studies have shown a reduction in hyperglycemia and A1C, without a concomitant increase in severe hypoglycemia.

Recent studies utilizing sensor-augmented pump therapy have shown no increase in hypoglycemia rates as mean A1C levels improve. The advent of this technology disputes the earlier findings of the landmark Diabetes Control and Complications Trial, which showed the relationship between decreasing diabetes complications by lowering A1C but at the expense of increasing severe hypoglycemia. This represents a great advance but shows there is still room to reduce hypoglycemia episodes even further.

This issue of hypoglycemia and its seriousness may have been best encapsulated in the recent full page newspaper ad the JDRF created and ran in both the New York Times and the Washington Post recently. According to the ad, one in 20 people will die from hypoglycemia. This statistic comes directly from JDRF, and certainly is staggering when contemplated. 

The point of the ad is not only to add a sense of gravity to the issue, but also confirm the important work being done on the artificial pancreas project. JDRF is leading the world in stimulating research in this area, and an artificial pancreas could address the hypoglycemia issue. The low glucose suspend feature is considered to be the first commercial development on the path to a comprehensive, artificial pancreas.

Medtronic, an international medical device company with a business unit that specializes in diabetes-related technologies, is the first company in the world thus far to create a product with low glucose suspend technology: the MiniMed Paradigm Veo insulin pump system.

Available in more than 50 countries internationally, but not in the U.S., the Paradigm Veo (pictured, upper left) has an LGS feature that automatically suspends insulin delivery for up to two hours upon reaching a predetermined threshold set up by the individual patient. The MiniMed Paradigm REAL-Time Revel system, which is what is currently available in the U.S., has features that alert someone when someone is about to reach a pre-set high or low threshold. However, the individual must take the necessary corrective actions, and the insulin pump does not go beyond alerting.

To date, three studies have been published in various journals. A study done by Medtronic by data mining the Carelink data base of almost 50,000 patient days of Veo usage, demonstrated the Veo’s efficacy in reducing the amount of time patients’ spent in both hypoglycemia and hyperglycemia.

The FDA has not yet approved an LGS product, but has recently given Medtronic an investigational device exemption (IDE) approval to conduct an in-home study, titled ASPIRE (Automation to Simulate Pancreatic Insulin Response) with its MiniMed Paradigm system, using the same LGS feature as the Veo`s.

Francine Kaufman, MD, Chief Medical Officer and vice president of global clinical affairs for the Medtronic’s diabetes division is an endocrinologist and understands first-hand the struggles type 1 patients have with hypoglycemia. Episodes of severe low blood glucose can lead to confusion and seizures, as well as result in high swings of the glucose value. One of the big-picture goals for the full artificial pancreas is to address these extreme abnormalities of glucose levels, and keep people in the acceptable, target range throughout the day and night. 

Understanding the potential quality-of-life ramifications along with the significant safety component such a system could offer U.S. patients, recently sat down with Dr. Kaufman (shown right) to discuss how the LGS  feature works in the Paradigm Veo system, the parameters of the ASPIRE study, and when an insulin pump with LGS could potentially be available on the U.S. market. Can you provide an overview of how the low glucose suspend feature will work in the insulin system being used in the ASPIRE Study?

Dr. Kaufman: It is a feature that can be turned on or off. If you choose to turn it on, the insulin pump will ask you at what threshold you want this suspend to occur. In the Paradigm Veo, the thresholds are from 40 to 110 mg/dl. Therefore, with their healthcare provider, patients would decide what threshold is best for patients looking at variety of factors.

Once your glucose sensor hits that level, it suspends insulin delivery and sets off an alarm. If your are awake, he or she will view this as a hypoglycemia alert; the patient will shut it off, and take a glass of juice or whatever you normally do to mitigate hypoglycemia.

The real purpose of this is for when someone doesn’t respond, it will suspend insulin delivery. So if you are sleeping and you don’t hear the alarm, or if you have hypoglycemic unawareness, this product will suspend all insulin delivery for two hours--unless you interrupt it earlier. At the end of the two hours, it will go back to the pre-set basal rates regardless of your glucose level for four hours. The cycle repeats if you are still low at the end of that four hour period. What is the timeline for the ASPIRE Study and the overall parameters for the patients who will be utilizing the study?

Dr. Kaufman: We are going to start as soon as we can, possibly in December. We have to enroll a fair number of patients. We anticipate the trial might take 18 to 24 months. We then submit the premarket approval (PMA) application and the FDA can have up to one year in the decision process.

Right now, we have 20 study sites across the US, and we are excited to partner with these investigators and their patients to conduct the ASPIRE study. What findings or statistics can you report about the Paradigm Veo?

Dr. Kaufman: There are now three published reports on the Veo. The first report  was a user evaluation done in the UK. They evaluated the Veo in 31 patients, and they showed in those who had hypoglycemia, there was a significant reduction. In addition, 93 percent of the subjects reported feeling more secure at night using the product.

Another study was conducted by Thomas Danne, MD, at three pediatric sites in Germany. They studied 21 pediatric patients who all had the low glucose suspend threshold set at 70 mg/dL. When the LGS feature was turned on, there was a reduction of time spent in both hyperglycemia and hypoglycemia, and a reduction in A1c.

A third study was done internally from data mining our CareLink database. 50,000 days and nights in over 900 patients were analyzed. The study showed a significant reduction in the amount of time spent under 50 mg/dl with most people setting the LGS between 50 and 60 mg/dl with a LGS episode occurring every 1 to 2 days.

On average, when insulin delivery is suspended with LGS, the glucose level starts to go up by 30 minutes, and increases about 20 mg/dl an hour to resolve hypoglycemia. Of all the low glucose suspends, the peak time for suspending was around lunchtime and the peak time for the full 2-hour suspend—which occurred in only about 10 to 12 percent of the suspends—was at night. If we can assume an insulin pump with LGS is able to come to the U.S. market, what would this system do that is different from past pump systems?

Dr. Kaufman: This would be the first automated step with the sensor data driving how the pump functions. It may be a first baby step, but an important first in automating some aspect of insulin delivery.

The FDA views it as part of a closed loop system or the artificial pancreas. We are now going to be busy doing this critical study to show hopefully what we have already shown in smaller studies, that the low glucose suspend feature will decrease the duration and severity of hypoglycemia without increasing hyperglycemia. What are your hopes for a timeline for when we might see an insulin pump with LGS available to Americans?

Dr. Kaufman: It is likely that it is more than two years away, but perhaps up to three years away. Although we have projections, a clinical trial can always take longer. If the FDA chooses to spend a year evaluating our submission, it could be three years. If things go better than expected, we might be able to knock off six months.