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JOURNAL CLUB 9/22/2014 Automated Glycemic Control : A New milestone in the management of type I diabetes?? Presenter: Sowmya Chandra Reddy PGY-3 Internal Medicine
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JOURNAL CLUB 9/22/2014Automated Glycemic Control : A New milestone in the management of type I diabetes??

Presenter:

Sowmya Chandra Reddy

PGY-3 Internal Medicine

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Importance of Glycemic control in type I DM:

Two landmark studies in the management of Type 1 DM:

DCCT (The Diabetes Control and Complications Trial) in 1993 and EDIC (The Epidemiology of Diabetes Interventions and Complications) trial in 2005 have demonstrated that improved glycemic control with intensive insulin therapy in patients with type 1 diabetes mellitus led to graded reductions in

retinopathy (by 76%)

nephropathy (by 40-50%),

neuropathy (by 60%) and

cardiovascular morbidity and mortality (by 40-50%) compared to conventional therapy.

This studies led to current practice of Intensive insulin therapy.

*The intensive-therapy regimen was designed to achieve blood glucose values as close to the normal range as possible with three or more daily insulin injections or treatment with an insulin pump.

*Conventional therapy consisted of one or two insulin injections per day.

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The biggest concern of Intensive Insulin therapy?

Hypoglycemia

Defined as all episodes of an abnormally low plasma glucose concentration (with or without symptoms) that expose the individual to harm. Those on Insulin the cut off is usually at (SMBG) level ≤70 mg/dL.

Population-based data indicate that patients with T1DM suffer ~1-3 episodes of severe hypoglycemia per year. [1,2]

Older estimates were that 2-4% of people with T1DM died from hypoglycemia. More recent estimates are that 4-10% [3-6] of deaths were due to hypoglycemia.

1Donnelly LA, et al. Diabet Med 22:749, 2005.

2UK Hypo Study Group. Diabetologia 50:1140, 2007.

3Diabetologia 50:2439, 2007.

4New Engl J Med 356:1842, 2007.

5Diabetes Care 31:922, 2008.

6Diabetologia 49:298, 2006

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Response to hypoglycemia and the role of glucagon :

Cryer PE. N Engl J Med 2013;369:362-372

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Schematic Diagram of Hypoglycemia-Associated Autonomic Failure (HAAF) in Diabetes.

Cryer PE. N Engl J Med 2013;369:362-372.

Figure 2.. Although marked insulin

excess can cause occasional episodes of hypoglycemia in patients with relative beta-

cell failure, less marked insulin excess often causes hypoglycemia in patients

with hypoglycemia-associated autonomic failure (defective glucose counter

regulation and hypoglycemia unawareness).

Adapted from Cryer.4

Schematic Diagram of Hypoglycemia-Associated

Autonomic Failure (HAAF) in Diabetes

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Overview of Current Insulin therapy in type I diabetes: Multiple daily injections versus Continuous Insulin therapies:

1. Multiple daily injections(MDI) : Basal + Bolus dosing

approximately one-half of the total dose should be given as a basal insulin, either as once or twice per day with long-acting / intermediate acting insulin and pre meal bolus insulin as below.

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Multiple daily injections(MDI)

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Continuous Subcutaneous Insulin Pump:

Basal insulin is supplied in the form of a continuous infusion (40 to 60 percent of the total daily dose) with pre-meal bolus doses given to minimize postprandial glucose excursions.

Usually only short acting or very rapid acting insulin are used.

Types: Conventional Insulin pump(CSII) Sensor-augmented insulin pump (CSII with

Continuous Glucose Monitoring) Automated closed-loop insulin pump??

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Cont. Conventional subcutaneous Insulin pump

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Sensor-augmented insulin pump(CSII + CGM) – which is in use currently

Continuous subcutaneous insulin in conjunction with a continuous glucose monitoring (CGM) device to give the patient more information about their blood glucose levels and allow them to make better informed decisions about insulin dosing.

Advantages: A randomized trial compared sensor-augmented insulin pump therapy with MDI in 329 adults. After one year, the

reduction in mean A1C was significantly greater in the pump therapy group . The improvement in glycemic controls was not associated with an increase in the rate of severe hypoglycemia.

These results suggest that CSII in conjunction with continuous glucose monitoring may effectively improve glycemia while limiting the rise in hypoglycemia that often accompanies improved glycemic control.[1]

[1] Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, Joyce C, Peoples T, Perkins BA, Welsh JB, Willi SM, Wood MA, STAR 3 Study Group. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med. 2010;363(4):311

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Automated closed-loop insulin pump??Currently investigated

Studies are currently evaluating the efficacy of a fully automated closed-loop system of insulin delivery based upon continuous glucose sensing.

Only a few of the studies have examined the utility of these devices during eating and

usual daily activities; most have examined overnight control.  Recently, fully automated bihormonal(insulin and glucagon) closed-loop system has also

been evaluated in the outpatient setting over a period of time Our current article.

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Advantages of Insulin pump:

A randomized trial in 32 children and adolescents (aged 8 to 21 years) with type 1 diabetes showed that lower A1C and premeal glucose levels were more achievable with CSII than with an insulin regimen using once daily insulin glargine and premeal insulin aspart [1].

Insulin pump therapy allows more flexibility in the timing of meals as compared to multiple daily injections especially if NPH insulin is used.

Insulin absorption with pump therapy is less variable from day to day and therefore blood glucose profiles may be more predictable.

Dosing of small doses of insulin can be achieved with CSII not possible with syringes or pens. Doses as low as 0.05 units can be accurately delivered with CSII.

[1] Doyle EA, Weinzimer SA, Steffen AT, Ahern JA, Vincent M, Tamborlane WV. A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine.

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Journal article:

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Research Question:

FEASIBILITY OF OUTPATIENT AUTOMATED CLOSED LOOP BLOOD GLUCOSE CONTROL WITH A BI-HORMONAL “BIONIC” PANCREAS (INSULIN + GLUCOGON).

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Study description

A pilot study involving two 5-day trials. One involving adults and one involving adolescents, in which they tested an autonomous, wearable, bi-hormonal, ‘bioni’ pancreas in two distinct outpatient settings. Study type: Interventional cohort based study. Study Design: Random-order, crossover

design. (A crossover study is a longitudinal study in which subjects receive a sequence of different treatments)

Setting: Single center in Boston

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Importance/Relevance: To validate the results of glycemic control

noticed in previous inpatient overnight studies with automated bi- hormonal bionic pancreas in outpatient environment with flexible diet and exercise pattern.

The small short term studies resulted in following –

Near normal glucose levels with the use of a bihormonal (insulin and glucagon) closed-loop

system and reduced risk of hypoglycemia.

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 Study Methods:

Inclusion criteria Atleast1-year history of type 1 diabetes

mellitus and were receiving insulin-pump therapy

At least 21 years of age for adults(Beacon Hill study)

Adolescents ages of 12 and 21 years(Summer camp study)

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Exclusion criteria

Current participation in another diabetes related clinical trial

Pregnancy

History of cystic fibrosis, pancreatitis, or other pancreatic diseases

stimulated C-peptide > 0.1 nmol/l at 90 minutes after liquid mixed meal by the DCCT protocol??

total daily dose of insulin > 1.5 units/kg/day.

Hypoglycemia unawareness defined as lack of symptoms with plasma glucose (PG) levels < 50 mg/dl.

end stage renal disease on dialysis.

body mass index < 18 or > 35.

coronary artery disease, heart failure, history of TIA or stroke,

seizure disorder or history of hypoglycemic seizure in the last 5 years.

use of medications for glycemic control other than insulin or medications that affected gastric motility.

Inability to perform at least 30 minutes of moderate exercise.

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STUDY ARMCONTROL

ARM

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Control arm Study armadult study

• Patients in the adult study lived at home, carried out their usual activities, and managed their diabetes with their own insulin pump and, if desired, their own continuous glucose monitor.

• Patients wore a G4 Platinum continuous glucose monitor with alarms deactivated and glucose levels masked; it was calibrated with a point-of-care glucometer (HemoCue) twice daily.

• They kept a diary documenting hypoglycemic episodes, carbohydrate interventions, and exercise.

• Patients were given a food allowance and encouraged to eat restaurant meals.

• Patients were free to move about within an 8-km2 (3-mi2) area surrounding the Beacon Hill neighborhood in Boston and were accompanied by study staff members. During nighttime hours (from 11 p.m. to 7 a.m.), patients stayed in a hotel.

• At night venous plasma glucose levels measured every 30 minutes (every 15 minutes when plasma glucose levels were <70 mg per deciliter [3.9 mmol per liter]) with an autosampling glucose monitor (GlucoScout, International Biomedical), which study staff monitored by means of telemetry.

• From 7 a.m. to 11 p.m., fingerstick plasma glucose levels were measured with the HemoCue every 2 hours, before meals, and every 30 minutes during exercise and if the patient had symptoms during a hypoglycemic episode.

• Patients could consume carbohydrates at will for symptoms of hypoglycemia (with such consumption counted as an intervention if plasma glucose levels were <70 mg per deciliter) and were required to consume 15 g of carbohydrates if they had a plasma glucose value of less than 50 mg per deciliter (2.8 mmol per liter).

• During the overnight period, patients were awakened and given 15 g of carbohydrates if they had a venous plasma glucose value of less than 50 mg per deciliter for 30 minutes or a one-time value of less than 40 mg per deciliter (2.2 mmol per liter)

• Encouraged to eat at will including restaurants and exercise at will

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Summer camp study

Patients in the adolescent study participated in the same activities, ate the same meals, and stayed in the same cabins as nonparticipants in the diabetes camp.

During the control period, patients wore a masked continuous glucose monitor plus iPhone device. They used their own insulin pumps and, if desired, their own continuous glucose monitors.

Otherwise rest of the protocol were same for both arms.

Fingerstick plasma glucose measurements were obtained with the HemoCue before meals, at bedtime, at midnight, at approximately 3:45 a.m., before swimming or showering, and during hypoglycemic episodes with symptoms.

Patients consumed 15 g of carbohydrates if they had a plasma glucose value of less than 60 mg per deciliter (3.3 mmol per liter) or a value of less than 80 mg per deciliter (4.4 mmol per liter) that was accompanied by symptoms. These episodes were counted as interventions if plasma glucose levels were less than 70 mg per deciliter.

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Pre specified outcomes Co- primary outcomes for the adult study and adolescents were:- the average of scheduled plasma glucose levels (but only on bionic pancreas

arm in adults) and - the mean percentage of time that these levels were below 70 mg per deciliter

during the bionic-pancreas period and the control period for both groups

Secondary outcomes for both the adult and adolescent studies included- the number of carbohydrate interventions for hypoglycemic episodes-the mean glucose level as measured with the use of continuous glucose

monitoring-the time in clinically relevant glucose ranges and the fraction of patients with a

mean glucose level that was consistent with the therapeutic goals issued by the American Diabetes Association

* For bionic period days 2 to 5 were more representative due to adaptive nature of the bionic pancreas

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Statistics

 Comparisons between study groups were performed with the paired-sample, heteroskedastic Student's t-test

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Distributions of Mean Glucose Levels and Hypoglycemia among Adults and Adolescents on continuous glucose monitoring

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Discussion

In nut shell:

Study done in outpatient setting with flexibility of meals and exercise(under close monitoring for safety).

Both studies with reduced mean glucose levels of plasma glucose and blood glucose on CGM as compared to insulin pump therapy.

Decreased hypoglycemic episodes in adults . Among adolescents even though no difference in hypoglycemia achieved , there were less interventions for hypoglycemic episodes in the study arm as compared to control arm

More fraction of the time in the euglycemic range Decreased nocturnal hypoglycemic episodes More physiologic treatment for hypoglycemia with

glucagon ??

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Limitations

Adult patients were limited to moderate alcohol intake; higher alcohol intake might compromise the effectiveness of glucagon.

Given the close monitoring by study staff throughout the

adolescents study and during the bionic-pancreas period of the adult study, carbohydrate interventions for hypoglycemia may have been given more frequently or earlier than they would have been without supervision.

There were intermittent problems with wireless connectivity these missed doses may have led to hypoglycemia that could otherwise have been prevented?

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Limitations:

The bionic pancreas include a risk of hypoglycemia if acetaminophen ingestion leads to overestimation of the blood glucose level.

The long-term safety of peripheral micro dose glucagon administration has not been established.

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Future direction

More studies with greater number of patients involved in the study.

Improved device quality and pump integration Improvement in glucagon: currently glucagon

is unstable and has to be reconstituted every day

Long term safety of peripheral glucagon. Long term benefits on the complications of

diabetes as compared to Insulin pumps correctly being used.

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Disadvantages of Insulin pump as supposed to multiple daily injections

The costs of the pump and supplies are higher than those of ordinary syringes and needles.

Complications of pump therapy may include superficial infection or system failure.

System failure is usually due to blockage or leakage in the syringe or the infusion set or connectors, causing an interruption of infusion flow

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Currently

Condition Intervention Phase

Diabetes Mellitus Type 1

Device: Bionic PancreasDevice: Patient controlled insulin pump

Phase 2

A Multicenter Study of Outpatient Automated Blood Glucose Control With a Bihormonal Bionic PancreasThis study is currently recruiting participants.

Sponsor:Massachusetts General Hospital Collaborator:Boston UniversityInformation provided by (Responsible Party):Steven J. Russell, MD, PhD, Massachusetts General Hospital

     PurposeThis study will test the hypothesis that a wearable bionic pancreas system that automatically delivers insulin and glucagon can provide superior regulation of glycemia vs. usual care for adults with type 1 diabetes.

Massachusetts General Hospital in Boston, MA; University of Massachusetts Medical Center in Worcester, MA; University of North Carolina in Chapel Hill, NC; Stanford University in Palo Alto, CA.

The goal of the authors is that they would like the device to be approved by FDA by the end 2017!!!

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Thank you Moderator: Dr. Agarwal, Monica