Cannula pretreatment reduces hypoglycemia in insulin pump users

VIENNA – Pretreating cannulas with a recombinant human hyaluronidase reduces the risk of hypoglycemia in patients with type 1 diabetes using insulin pumps, according to the results of a phase IV study.

In CONSISTENT-1 (Continuous Subcutaneous Insulin Infusion Study Enrolling Type 1), there were 23% fewer hypoglycemic events, defined as a blood glucose level below 56 mg/dL, and 21% fewer nocturnal hypoglycemic events in patients who received the infusion site pretreatment, compared with those who did not.

Importantly, the primary endpoint of noninferiority for glycemic control after 6 months was achieved, with comparable final mean and mean change from baseline hemoglobin A_1c results.

“Current rapid-acting analogue insulin preparations are too slow to mimic the physiologic insulin meal response,” Dr. Jay Skyler, a study investigator with the University of Miami, explained at the annual meeting of the European Association for the Study of Diabetes.

He noted that hyaluronidase has been used for more than 60 years and recombinant human hyaluronidase (rHuPH20) is approved by the Food and Drug Administration as a means of improving the dispersion and absorption of injected or infused drugs. “Previously, we have demonstrated that adding recombinant human hyaluronidase [Halozyme Therapeutics’ Hylex] to rapid-acting insulin preparations accelerates the absorption and action of insulin,” Dr. Skyler said.

In this study, rHuPH20 was given in a single injection into the cannula prior to the placement of a pump for continuous subcutaneous insulin infusion (CSII), but Dr. Skyler observed that it could also be coformulated with insulin for use in pens or vials.

The aim of CONSISTENT-1 was to assess the metabolic outcomes and safety of rHuPH20 after 6 months. The trial was open label, and 456 patients with type 1 diabetes were randomized, in a 3 to 1 ratio, to pretreatment with rHuPH20 or to standard CSII without rHuPH20.

The mean age of participants was 47 years in the rHuPH20 arm and 50 years in the CSII-alone arm. Around a quarter of patients in each group used continuous glucose monitors (CGMs), and 77% had used an insulin pump for more than 5 years. Patients had been using insulin pumps for a mean of about 10 years in both groups.

The number of hypoglycemic events per month was 13.8 in the rHuPH20-pretreated group and 12.1 in the CSII-only group when a blood glucose cutoff of 70 mg/dL or lower was used, representing a nonsignificant 12% reduction. However, when the lower threshold of 56 mg/dL or lower was used, there were fewer hypoglycemia events per month (4.0 vs. 3.1; P = .02).

While the difference in the number of nocturnal hypoglycemic events per month between the rHuPH20 and CSII-only groups was also significant (2.1 vs. 1.7; P = .02), the rate of severe hypoglycemic events per 100 subject-years was only numerically lower (19 vs. 7; P = .08) in the rHuPH20 group.

Subgroup analysis showed that the timing of bolus dosing was important, with fewer blood glucose excursions and hypoglycemic events if insulin was dosed within 15 minutes before a meal than if it was dosed within 15 minutes after a meal.

Looking at CGM profiles for breakfast, lunch, and dinner, there were fewer glucose excursions in the patients who had received rHuPH20, and, stating that it was the reason for performing the study, Dr. Skyler said there were fewer excursions on subsequent days.

In terms of safety, he noted that there was an increase in injection-site reactions in the rHuPH20-pretreated group, with pain, discomfort, or paresthesia in 15.5%, compared with 6.2% in the CSII-only patients. In addition, hematoma, bruising, or hemorrhage occurred in 3.8% of the rHuPH20 group vs. 0.0% of the standard CSII group. There was no “meaningful immunogenicity,” and adverse events were otherwise well balanced between the groups.

Dr. Skyler said that a 1.5-year extension study is in progress and that the current findings “demonstrate that rHuPH20 pretreatment eliminates the systemic variability in glucose control that naturally occurs as infusion sites age.

“This should allow for improved diabetes control since insulin responses will occur more predictably.”

Halozyme supported the study. Dr. Skyler has been an adviser for Halozyme and has consulted for other companies with an interest in insulin pump therapy.

VIENNA – Pretreating cannulas with a recombinant human hyaluronidase reduces the risk of hypoglycemia in patients with type 1 diabetes using insulin pumps, according to the results of a phase IV study.

In CONSISTENT-1 (Continuous Subcutaneous Insulin Infusion Study Enrolling Type 1), there were 23% fewer hypoglycemic events, defined as a blood glucose level below 56 mg/dL, and 21% fewer nocturnal hypoglycemic events in patients who received the infusion site pretreatment, compared with those who did not.

Importantly, the primary endpoint of noninferiority for glycemic control after 6 months was achieved, with comparable final mean and mean change from baseline hemoglobin A_1c results.

“Current rapid-acting analogue insulin preparations are too slow to mimic the physiologic insulin meal response,” Dr. Jay Skyler, a study investigator with the University of Miami, explained at the annual meeting of the European Association for the Study of Diabetes.

He noted that hyaluronidase has been used for more than 60 years and recombinant human hyaluronidase (rHuPH20) is approved by the Food and Drug Administration as a means of improving the dispersion and absorption of injected or infused drugs. “Previously, we have demonstrated that adding recombinant human hyaluronidase [Halozyme Therapeutics’ Hylex] to rapid-acting insulin preparations accelerates the absorption and action of insulin,” Dr. Skyler said.

In this study, rHuPH20 was given in a single injection into the cannula prior to the placement of a pump for continuous subcutaneous insulin infusion (CSII), but Dr. Skyler observed that it could also be coformulated with insulin for use in pens or vials.

The aim of CONSISTENT-1 was to assess the metabolic outcomes and safety of rHuPH20 after 6 months. The trial was open label, and 456 patients with type 1 diabetes were randomized, in a 3 to 1 ratio, to pretreatment with rHuPH20 or to standard CSII without rHuPH20.

The mean age of participants was 47 years in the rHuPH20 arm and 50 years in the CSII-alone arm. Around a quarter of patients in each group used continuous glucose monitors (CGMs), and 77% had used an insulin pump for more than 5 years. Patients had been using insulin pumps for a mean of about 10 years in both groups.

The number of hypoglycemic events per month was 13.8 in the rHuPH20-pretreated group and 12.1 in the CSII-only group when a blood glucose cutoff of 70 mg/dL or lower was used, representing a nonsignificant 12% reduction. However, when the lower threshold of 56 mg/dL or lower was used, there were fewer hypoglycemia events per month (4.0 vs. 3.1; P = .02).

While the difference in the number of nocturnal hypoglycemic events per month between the rHuPH20 and CSII-only groups was also significant (2.1 vs. 1.7; P = .02), the rate of severe hypoglycemic events per 100 subject-years was only numerically lower (19 vs. 7; P = .08) in the rHuPH20 group.

Subgroup analysis showed that the timing of bolus dosing was important, with fewer blood glucose excursions and hypoglycemic events if insulin was dosed within 15 minutes before a meal than if it was dosed within 15 minutes after a meal.

Looking at CGM profiles for breakfast, lunch, and dinner, there were fewer glucose excursions in the patients who had received rHuPH20, and, stating that it was the reason for performing the study, Dr. Skyler said there were fewer excursions on subsequent days.

In terms of safety, he noted that there was an increase in injection-site reactions in the rHuPH20-pretreated group, with pain, discomfort, or paresthesia in 15.5%, compared with 6.2% in the CSII-only patients. In addition, hematoma, bruising, or hemorrhage occurred in 3.8% of the rHuPH20 group vs. 0.0% of the standard CSII group. There was no “meaningful immunogenicity,” and adverse events were otherwise well balanced between the groups.

Dr. Skyler said that a 1.5-year extension study is in progress and that the current findings “demonstrate that rHuPH20 pretreatment eliminates the systemic variability in glucose control that naturally occurs as infusion sites age.

“This should allow for improved diabetes control since insulin responses will occur more predictably.”

Halozyme supported the study. Dr. Skyler has been an adviser for Halozyme and has consulted for other companies with an interest in insulin pump therapy.

VIENNA – Pretreating cannulas with a recombinant human hyaluronidase reduces the risk of hypoglycemia in patients with type 1 diabetes using insulin pumps, according to the results of a phase IV study.

In CONSISTENT-1 (Continuous Subcutaneous Insulin Infusion Study Enrolling Type 1), there were 23% fewer hypoglycemic events, defined as a blood glucose level below 56 mg/dL, and 21% fewer nocturnal hypoglycemic events in patients who received the infusion site pretreatment, compared with those who did not.

Importantly, the primary endpoint of noninferiority for glycemic control after 6 months was achieved, with comparable final mean and mean change from baseline hemoglobin A_1c results.

“Current rapid-acting analogue insulin preparations are too slow to mimic the physiologic insulin meal response,” Dr. Jay Skyler, a study investigator with the University of Miami, explained at the annual meeting of the European Association for the Study of Diabetes.

He noted that hyaluronidase has been used for more than 60 years and recombinant human hyaluronidase (rHuPH20) is approved by the Food and Drug Administration as a means of improving the dispersion and absorption of injected or infused drugs. “Previously, we have demonstrated that adding recombinant human hyaluronidase [Halozyme Therapeutics’ Hylex] to rapid-acting insulin preparations accelerates the absorption and action of insulin,” Dr. Skyler said.

In this study, rHuPH20 was given in a single injection into the cannula prior to the placement of a pump for continuous subcutaneous insulin infusion (CSII), but Dr. Skyler observed that it could also be coformulated with insulin for use in pens or vials.

The aim of CONSISTENT-1 was to assess the metabolic outcomes and safety of rHuPH20 after 6 months. The trial was open label, and 456 patients with type 1 diabetes were randomized, in a 3 to 1 ratio, to pretreatment with rHuPH20 or to standard CSII without rHuPH20.

The mean age of participants was 47 years in the rHuPH20 arm and 50 years in the CSII-alone arm. Around a quarter of patients in each group used continuous glucose monitors (CGMs), and 77% had used an insulin pump for more than 5 years. Patients had been using insulin pumps for a mean of about 10 years in both groups.

The number of hypoglycemic events per month was 13.8 in the rHuPH20-pretreated group and 12.1 in the CSII-only group when a blood glucose cutoff of 70 mg/dL or lower was used, representing a nonsignificant 12% reduction. However, when the lower threshold of 56 mg/dL or lower was used, there were fewer hypoglycemia events per month (4.0 vs. 3.1; P = .02).

While the difference in the number of nocturnal hypoglycemic events per month between the rHuPH20 and CSII-only groups was also significant (2.1 vs. 1.7; P = .02), the rate of severe hypoglycemic events per 100 subject-years was only numerically lower (19 vs. 7; P = .08) in the rHuPH20 group.

Subgroup analysis showed that the timing of bolus dosing was important, with fewer blood glucose excursions and hypoglycemic events if insulin was dosed within 15 minutes before a meal than if it was dosed within 15 minutes after a meal.

Looking at CGM profiles for breakfast, lunch, and dinner, there were fewer glucose excursions in the patients who had received rHuPH20, and, stating that it was the reason for performing the study, Dr. Skyler said there were fewer excursions on subsequent days.

In terms of safety, he noted that there was an increase in injection-site reactions in the rHuPH20-pretreated group, with pain, discomfort, or paresthesia in 15.5%, compared with 6.2% in the CSII-only patients. In addition, hematoma, bruising, or hemorrhage occurred in 3.8% of the rHuPH20 group vs. 0.0% of the standard CSII group. There was no “meaningful immunogenicity,” and adverse events were otherwise well balanced between the groups.

Dr. Skyler said that a 1.5-year extension study is in progress and that the current findings “demonstrate that rHuPH20 pretreatment eliminates the systemic variability in glucose control that naturally occurs as infusion sites age.

“This should allow for improved diabetes control since insulin responses will occur more predictably.”

Halozyme supported the study. Dr. Skyler has been an adviser for Halozyme and has consulted for other companies with an interest in insulin pump therapy.