Safety, Tolerability of Dasiglucagon Examined for Severe Hypoglycemia


OBJECTIVE

Treatment of severe hypoglycemia outside of the hospital setting is limited to glucagon formulations requiring reconstitution before use, which may lead to erroneous or delayed glucagon administration. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and safety and tolerability of different doses of dasiglucagon, a novel soluble glucagon analog, with approved pediatric and full doses of GlucaGen in insulin-induced hypoglycemia in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

In this single-center, randomized, double-blind trial, 58 patients with type 1 diabetes received single subcutaneous injections of 0.1, 0.3, 0.6, or 1.0 mg dasiglucagon or 0.5 or 1.0 mg GlucaGen in a state of hypoglycemia (blood glucose target 55 mg/dL) induced by an intravenous insulin infusion.

RESULTS

Dasiglucagon demonstrated a dose-dependent and rapid increase in plasma concentrations, reaching a maximum at ∼35 min with a half-life of ∼0.5 h. Dasiglucagon rapidly increased plasma glucose (PG) by ≥20 mg/dL (9–14 min) to PG ≥70 mg/dL (within 6–10 min), similar to GlucaGen, but with a longer-lasting and greater effect on PG. All patients on both treatments reached these end points within 30 min (predefined success criteria). Both treatments were well tolerated. Nausea was the most frequent adverse event, occurring at a similar rate (44–56%).

CONCLUSIONS

Dasiglucagon was well tolerated and showed an early PD response similar to that of GlucaGen at corresponding doses, suggesting comparable clinical effects of the two glucagon formulations. Dasiglucagon has the potential to become an effective and reliable rescue treatment for severe hypoglycemia in a ready-to-use pen.

Study: Too Much Hypoglycemia in Diabetic Hospice Patients


This despite guidelines calling for relaxed glycemic control in hospice

When it comes to hospice patients with type 2 diabetes, avoiding hypoglycemia may be more important than strict glycemic control, researchers argued.

In a researcher letter appearing in JAMA Internal Medicine, about 12% of hospice patients with type 2 diabetes residing in nursing home experienced hypoglycemia within 180 days of admission — a glucose reading under 70 mg/dL.

As for severe hypoglycemia — a glucose reading under 50 mg/dL — this was experienced by approximately 5% of hospice patients in nursing homes within 180 days of admission, reported Laura A. Petrillo, MD, of Massachusetts General Hospital in Boston, and colleagues.

The risk was even greater for those receiving insulin: cumulative incidence of 38% for all hypoglycemia and 18% for severe episodes within 180 days of admission, with the peak risk occurring during the initial 20 days. Hyperglycemia incidence was 9% overall; 35% among those on insulin.

“[H]ypoglycemia is not consistent with a goal of comfort, and these data demonstrate suboptimal avoidance of dysglycemia among patients with type 2 diabetes on hospice in nursing homes,” wrote Petrillo and colleagues.

According to the 2016 guidelines from the American Diabetes Association, people with diabetes receiving end-of-life care should relax glycemic control targets and eventually discontinue diabetes medication in order to avoid hypoglycemia, which Petrillo’s group calls a “potentially preventable cause of suffering among hospice patients.”

The retrospective cohort study included 20,329 hospice patients with type 2 diabetes admitted to Veterans Affairs nursing homes between 2006 to 2015. All patients either had an HbA1c over 6.5% or were identified with type 2 diabetes through an ICD-9 code. Patients with type 1 diabetes were excluded from the analysis.

The majority of hospice patients — nearly all of whom were male (98%) — were not being treated with insulin (91.7% no insulin vs. 8.3% on insulin). The most common comorbidities included hypertension (38%), cancer (35%), chronic kidney disease (24%), and chronic pulmonary disease (24%).

Use of an oral glucose lowering medication was relatively low among the total cohort (12%), while oral medication use was more common among patients on insulin (11% no insulin vs. 21% on insulin; P<0.001). Patients on insulin also had higher HbA1c levels at baseline (6.8% no insulin vs. 7.4% on insulin; P<0.001) and experienced more frequent glucose tests while in hospice (0.6 tests per day for vs. 1.7 tests per day on insulin; P<0.001). Only one-fifth of all patients had no HbA1c testing recorded — the majority of whom were not on insulin (21% no insulin vs. 12% on insulin; P<0.001).

The 100-day mortality rate among all patients was 83%, although death within 100 days of admission was significantly lower among patients treated with insulin (85% no insulin vs. 61% on insulin; P<0.001). Patients on insulin also had a longer median length of stay (10 days no insulin vs. 25 days on insulin; P<0.001).

“Patients treated with insulin lived longer and experienced more hyperglycemia than patients not treated with insulin, which suggests that clinicians may be choosing to continue insulin for those hospice patients with a longer life expectancy and more severe diabetes at hospice admission,” the research group noted.

In regards to future research, the group recommended additional studies are required to “establish optimal timing of diabetes medication titration and cessation,” as well as to “characterize the effect of hypoglycemia and hyperglycemia on the symptom burden of patients with diabetes on hospice.”

Automated glucagon delivery reduces hypoglycemia in type 1 diabetes


Patients with type 1 diabetes receiving glucagon from an automatic bionic pancreas experienced fewer symptomatic hypoglycemia episodes compared with those receiving placebo, according to a presenter here.

Courtney Balliro, RN, BS, CDE, a clinical research at Massachusetts General Hospital Diabetes Research Center, and colleagues evaluated data from 22 adults with type 1 diabetes who used an insulin pump or multiple daily injections and had reduced hypoglycemia awareness.

Participants administered their own insulin but were randomly assigned to glucagon or placebo (randomized daily) from an automated bionic pancreas. The primary outcome measure was area over the curve (AOC) and blood glucose less than 60 mg/dL.

AOC less than 60 mg/dL was reduced by 75% on glucagon days compared with placebo days (P < .001) and by 91% at night (P < .0001). Symptomatic hypoglycemia episodes were half the amount on glucagon days (0.6 incidents per day) compared with placebo days (1.2 incidents per day; P < .0001); however, there was no difference in mean continuous glucose monitoring.

No unexpected or severe adverse events were reported during either treatment.

“We expected the device to prevent low blood sugar; however, we were pleasantly surprised by its efficacy,” Balliro said during her presentation. “This device has the potential to simplify the lives of people with any disorder that causes low blood glucose levels by providing automatic treatment. Automatic treatment of hypoglycemia is particularly important for people with diabetes due to their increased risk for significant complications.” – by Amber Cox

Bionic pancreas effective in home setting for reducing glucose, hypoglycemia


Use of a bionic pancreas was associated with reductions in mean glucose and hypoglycemia compared with conventional insulin pump therapy, when used in the home setting by adults with type 1 diabetes.

“This was our first true home-study,” Edward R. Damiano, PhD, professor of biomedical engineering at Boston University, said during a presentation at the American Diabetes Association Scientific Sessions. “All participants lived at home and went to work, and there were no restrictions on diet or exercise.”

Edward Damiano

Edward R. Damiano

Damiano and colleagues sought to determine the efficacy of continuous, multi-day, automated glycemic control using a bihormonal bionic pancreascompared with conventional insulin pump therapy in adults with type 1 diabetes living at home and performing normal activities. Glycemic regulation was compared between the bionic pancreas and insulin pump over 11 days each in all participants. During the bionic pancreas period, continuous glucose monitor (CGM) data were used by an autonomous adaptive algorithm to control subcutaneous insulin and glucagon delivery. During the pump period, patients managed their own conventional insulin pump therapy.

The mean reduction in glucose level was 162 mg/dL with the bionic pancreas compared with 141 mg/dL with the insulin pump (P < .0001). The bionic pancreas was also associated with greater reductions in time less than 60 mg/dL by CGM (1.9% vs. 0.6%; P < .0001).

In other results, the mean number of symptomatic hypoglycemia events was lower with the bionic pancreas: 0.59 events per day compared with 0.6 events per day (P = .023). The mean total daily dose of insulin was 6% greater with the bionic pancreas compared with the insulin pump (P = .01). – by Amber Cox

Bionic pancreas effective in home setting for reducing glucose, hypoglycemia


Use of a bionic pancreas was associated with reductions in mean glucose and hypoglycemia compared with conventional insulin pump therapy, when used in the home setting by adults with type 1 diabetes.

“This was our first true home-study,” Edward R. Damiano, PhD, professor of biomedical engineering at Boston University, said during a presentation at the American Diabetes Association Scientific Sessions. “All participants lived at home and went to work, and there were no restrictions on diet or exercise.”

Edward Damiano

Edward R. Damiano

Damiano and colleagues sought to determine the efficacy of continuous, multi-day, automated glycemic control using a bihormonal bionic pancreascompared with conventional insulin pump therapy in adults with type 1 diabetes living at home and performing normal activities. Glycemic regulation was compared between the bionic pancreas and insulin pump over 11 days each in all participants. During the bionic pancreas period, continuous glucose monitor (CGM) data were used by an autonomous adaptive algorithm to control subcutaneous insulin and glucagon delivery. During the pump period, patients managed their own conventional insulin pump therapy.

The mean reduction in glucose level was 162 mg/dL with the bionic pancreas compared with 141 mg/dL with the insulin pump (P < .0001). The bionic pancreas was also associated with greater reductions in time less than 60 mg/dL by CGM (1.9% vs. 0.6%; P < .0001).

In other results, the mean number of symptomatic hypoglycemia events was lower with the bionic pancreas: 0.59 events per day compared with 0.6 events per day (P = .023). The mean total daily dose of insulin was 6% greater with the bionic pancreas compared with the insulin pump (P = .01). – by Amber Cox

Service dogs can detect hypoglycemia, alert companion


Service dogs trained to identify hypoglycemia in their human companions can correctly identify the condition and sound a timely alert, according to study findings presented at the American Diabetes Association Scientific Sessions.

Evan Los

Evan A. Los

“Trained dogs often alert a human companion to otherwise unknown hypoglycemia; however, most alerts occurred when the patient did not actually have hypoglycemia. Continuous glucose monitoring often detects hypoglycemia before a trained dog by a clinically significant margin,” Los toldEndocrine Today.

According to Los, “patient-reported reliability painted a much more favorable assessment of the dog’s abilities than we actually found in the study. This has the potential to lead to over-reliance on a poorly performing diagnostic tool that has significant financial cost and time investment.”

Los and colleagues compared reliability of hypoglycemia alerts using fingerstick measures and blinded CGM for eight patients with type 1 diabetes aged 4 to 48 years who lived with service dog companions for the primary purpose of detecting hypoglycemia. Hypoglycemia was defined as blood glucose level below 70 mg/dL.

The service dogs — five Labrador retriever/lab mixes, one St. Bernard, one golden doodle and a collie, according to Los — scored high in patient satisfaction (8.9 of 10 on a Likert scale) and patient confidence (7.9 of 10) in their ability to alert to hypoglycemia.

Dogs alerted the patients 3.2 (95% CI, 2-5.2) times more often during hypoglycemia than during euglycemia. Among a total of 45 hypoglycemic events during the study period, dogs appropriately alerted in a timely manner (10 minutes before to 30 minutes after onset) in 36% of events. When both dog and CGM data indicated a hypoglycemic event (n = 30), CGM would have alerted the patient a median of 22 minutes earlier than the dog.

During a presentation of study results, Los said the dogs had been trained by different methods and may have been conditioned to alert at different glucose levels than the 70 mg/dL limit chosen by the researchers.

“This study helps equip clinicians to provide an answer to the question: ‘What do you think about diabetes alert dogs?’” Los said. “This is not the final word on whether trained dogs might be helpful for patients with diabetes, and there may be other benefits not assessed by this study, such as having a positive partner in the daily management of a chronic disease.” – by Jill Rollet

Adding Glucagon to Artificial Pancreas May Cut Hypoglycemia


Possible reduction in hypoglycemia in pooled small outpatient studies

 Using both a glucagon and insulin pump integrated with continuous glucose monitoring could reduce nighttime hypoglycemia in type 1 diabetes, a combined analysis of two small outpatient studies suggested.

Overnight use of the dual-hormone system was associated with less time spent in the hypoglycemic range under 72 mg/dL, at 1.0% compared with 3.1% with the single-hormone system and 5.1% with conventional insulin pump therapy, Ahmad Haidar, PhD, of McGill University in Montreal, and colleagues found.

The difference was almost entirely accounted for during the first half of the night, the time when glucagon was administered, whereas insulin delivery was otherwise similar between the two artificial pancreas systems.

Those were the findings from two randomized open-label crossover trials, one with 21 adults and seven children in a home setting using Medtronic pumps and sensors for two nights per intervention and the other with 33 children in a camp setting using Dexcom sensors and Roche pumps for 3 nights per intervention.

Combined analysis was reported here at the American Diabetes Association annual meeting, along with simultaneous publication of the pediatric camp study online inLancet Diabetes and Endocrinology.

The two artificial pancreas systems yielded similar overall glucose levels, both averaging 122 mg/dL compared with 140 mg/dL with conventional pump therapy.

Time spent at night in the hyperglycemic range over 144 mg/dL was 21% with the dual system, 23% with the single-hormone system, and 48% with conventional pump therapy.

The difference in nocturnal hypoglycemia was not significant in the pediatric study on its own, given the higher bar for statistical significance with multiple looks.

That study used a research-level set-up, with the kids’ continuous glucose monitors reading out to a sensor set outside the camp tent every 10 minutes, which was then entered manually by study staff into a tablet computer to run a dosing algorithm for the artificial pancreas systems that was then used to manually deliver the medications via remote control.

The researchers suggested that their findings warrant larger, longer studies with the goal of a fully integrated system.

Such a system would be more complex and more expensive, Jessica R. Castle, MD, of the Oregon Health & Science University in Portland, cautioned in an editorial accompanying the Lancet paper.

“Many advancements are needed to make a dual-hormonal automated system commercially viable,” she wrote, “including the approval of a stable glucagon formulation, a dual-chamber pump for combined storage and delivery of insulin and glucagon, and preferably a specialized infusion set that allows for combined delivery through a single insertion site.

“Despite these hurdles, the ongoing development of dual-hormonal systems is needed. Until a truly ultra-rapid insulin is available, an insulin-only system will be suboptimal, particularly in situations where insulin needs drop rapidly, such as during exercise.”

Hypoglycemia: the Unspoken Threat of Diabetes


The morning I began this post about the recent American Association of Diabetes Educators’ (AADE) survey that reveals many people with diabetes do not know what hypoglycemia (low blood sugar) is — I nearly gave it to myself.

Hypoglycemia is defined as blood sugar below 70 mg/d. (3.9 mmol/l). For people with diabetes who take insulin or another glucose (blood sugar) lowering medication – whether you have Type 1, Type 2, Gestational diabetes or LADA — there is a ’round-the-clock threat of your blood sugar dropping below 70.

For the first time in my nearly 43 years of living with diabetes I mixed up my two insulins. I take a long-acting insulin via an insulin pen and a mealtime insulin with vial and syringe. Two days ago I got an insulin pen for my mealtime insulin to see if I preferred it.

Without thinking, I injected eight units (my long-acting dose) of my mealtime insulin instead of 2 units (my breakfast dose). I immediately drank a quarter cup of maple syrup to counteract the expected drop in blood sugar (the rise you see to over 300 mg/dl (16.6 mmol/l) is the quick action of the maple syrup). The subsequent drop was the insulin kicking in.

cgmIf I hadn’t had the maple syrup, that more than 200-point drop could have killed me. Until my blood sugar stabilized within normal range, I watched it on my CGM and checked it on my meter every half hour.

Luckily I was able to save myself because I knew what to do. Unfortunately, too many people living with diabetes, had they made this same mistake, may not have been as lucky. Severe hypoglycemia, blood sugar below 40 mg/dl (2.2 mmol/l), can cause convulsions, seizures, a loss of consciousness and death.

Survey Results

Of the 1,000 survey participants, people with both Type 1 and Type 2 diabetes, one third did not know what hypoglycemia is and 42 percent couldn’t describe it. Among those who could, many did not know how to prevent or treat it.

If you think few people experience hypoglycemia, think again. Sixty percent of the study participants had experienced hypoglycemia and it took one third of them to the emergency room for treatment.

Almost half, 49 percent, did not know that a simple remedy, like taking glucose tablets, could help raise their blood sugar back to normal levels.

The survey results indicate that we’re failing people with diabetes not teaching them about hypoglycemia, and I see it as a shameful omission by healthcare providers.

Many health professionals delay putting patients on insulin, which might better manage their blood sugar and help them avoid complications, because of the time investment necessary to educate patients about using insulin — and the fear of a hypoglycemic event without that education.

At the same time, many people with diabetes keep their blood sugar unhealthfully high for fear of being rendered helpless by hypoglycemia.

Citing the lack of education around hypoglycemia, Dr. Evan Sisson, associate professor at the Virginia Commonwealth University’s School of Pharmacy and certified diabetes educator, told me over the past decade practitioners’ focus has been on correcting hyperglycemia, high blood sugar.

Accordingly, rates of hospital admission for hyperglycemia have significantly decreased. Unfortunately, Sisson says the rates of hypoglycemia have increased by almost 25 percent.

AADE and Sanofi U.S., who supported the study, say they’re working to raise awareness about hypoglycemia, but it can’t happen fast enough.

Don’t wait for your doctor to talk to you about hypoglycemia. Ask him or her if the medication you take puts you at risk for low blood sugar. If it does, ask what you need to know to recognize, prevent and treat hypoglycemia.

Islet transplantation restored glucose counter-regulation in patients with type 1 diabetes


Pancreatic islet cell transplantation can help patients with type 1 diabetes regain normal internal recognition ofhypoglycemia, following the loss of awareness that occurs with insulin treatments over time, according to research published in Diabetes.

“The results of this study suggest that islet cell transplantation may be an effective treatment for patients with type 1 diabetes who are experiencing significant hypoglycemic events because their body isn’t able to recognize their low blood sugar levels,” Michael R. Rickels, MD, director of the Pancreatic Islet Cell Transplant Program at University of Pennsylvania, Philadelphia.

“Currently, islet cell transplantation is considered investigational for type 1 diabetes patients, but this study shows that it has the potential to dramatically improve a patient’s ability to defend against and recognize symptoms of hypoglycemia and eliminate severe hypoglycemic episodes,” he said.

Rickels, with colleagues from the Perelman School of Medicine at the institution and the Monell Chemical Senses Center, also in Philadelphia, longitudinally studied 12 patients with hypoglycemia unawareness and frequent severe hypoglycemia who were assigned to one or two islet infusions to achieve insulin-independence; disease duration was approximately 30 years.

Prior to and 6 months after intrahepatic islet transplantation, the investigators assessed hypoglycemia recognition capability using stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-2H2-glucose, then compared results with those from a control group of 8 participants without diabetes.

HbA1c was normalized following islet transplantation. Further, time spent in hypoglycemia (<70

mg/dL) was nearly eliminated, based on continuous glucose monitoring.

In response to insulin-induced hypoglycemia, C-peptide, absent prior to transplant, was aptly suppressed, glucagon secretion recovered and epinephrine secretion improved following transplantation.

Consistent with hormonal changes, endogenous glucose production response to insulin-induced hypoglycemia, also absent prior to transplant, was normalized following; a similar effect was seen for autonomic symptoms.

“Now that we’ve seen improvement in the protection against hypoglycemia as a result of islet cell transplantation, we’re evaluating the longer-term durability of these restored defense mechanisms,” Rickels said in the release.

Fellow investigator Ali Naji, MD, PhD, also at Penn, aims to develop new immunosuppression medication approaches to reduce the risk for adverse side effects through work now being conducted in his laboratory.

Anti-hyperglycemic drug selection, sequence for type 2 diabetes addressed in ADA/EASD position statement update.


A revised position statement on the management of hypoglycemia in patients with type 2 diabetes, updated upon request from the American Diabetes Association and the European Association for the Study of Diabetes, is published in Diabetes Care.

The writing group that penned the guidelines published in 2012, when a paucity of comparative effectiveness research existed on the long-term treatment outcomes of anti-hyperglycemic drugs, reconvened from June to September 2014 to incorporate data from recent clinical trials.

“An entirely new statement was felt to be unnecessary,” according to the writing group. “Instead, the group focused on those areas where revisions were suggested by a changing evidence base.”

Silvio E. Inzucchi, MD, of Yale University School of Medicine, New Haven, Connecticut, with co-chair David R. Matthews, MD, University of Oxford, United Kingdom steered members’ input to address critical areas, including glycemic targets, therapeutic options, implementation strategies, other considerations and future directions.

Silvio Inzucchi

Silvio E. Inzucchi

The experts emphasized that studies have determined that reducing hyperglycemia decreased both the onset and progression of macrovascular complications, but they noted that the impact of glucose control on cardiovascular complications remains uncertain and stressed the importance of an individualized approach.

“Instead of a one-size-fits-all approach, personalization is necessary, balancing the benefits of glycemic control with its potential risks, taking into account the adverse effects of glucose-lowering medications (particularly hypoglycemia), and the patient’s age and health status, among other concerns,” they wrote.

The researchers noted that the availability of sodium glucose cotransporter 2 (SGLT2) inhibitors presents a major change in treatment options since the previous publication. They underscored that earlier concerns about thiazolidinediones (TZD) and bladder cancer have been allayed; however, they advised that dipeptidyl peptidase-4 (DPP-4) inhibitors be used cautiously in light of potential cardiovascular effects and highlighted the pancreatic safety concerns in this class as well as in glucagon-like peptide-1 (GLP-1) receptor agonists.

“The use of any drug in patients with type 2 diabetes must balance the glucose-lowering efficacy,

side-effect profiles, anticipation of additional benefits, cost and other practical aspects of care, such as dosing schedule and requirements for glucose monitoring,” they wrote.

The experts highlighted recent calls to relax prescribing policies to extend the use of metformin — still the first-line choice for monotherapy — in patients with mild to moderate kidney disease, and encouraged due caution for renal insufficiency when considering second-line agents.

In addressing dual and triple combination therapies, the researchers noted that no evidence-based recommendation can be made for using SGLT2 inhibitors in conjunction with GLP-1 receptor agonists without data. Although clinicians can look to additional drugs to treat patients with HbA1c levels well above target ≥9% (≥75 mmol/mol), no proven advantage has been shown by achieving a glycemic target more quickly, according to the writing group.

“As long as close patient follow-up can be ensured, prompt sequential therapy is a reasonable alternative, even in those with baseline HbA1c levels in this range,” they wrote.