Threshold-suspend/Low-glucose-suspend Insulin Delivery Systems for Managing Hypoglycemia in Patients with Type 1 Diabetes Mellitus

Proprietary names: Bayer Contour® Next Link meter, Bolus Wizard®, CareLink® Personal Therapy Management Software for Diabetes, CareLink Pro Therapy Management Software for Diabetes, Enlite™ Sensor, Enlite Serter, MiniLink® Real-Time System, MiniMed® 530G System, MiniMed 530G System with Enlite, MiniMed 530G System with Enlite Sensor, MiniMed Paradigm™ System, MiniMed Paradigm Veo™ System, MiniMed Veo System, Paradigm® Revel™ Insulin Pump

Generic names: artificial pancreas device system (APDS), low-glucose suspend (LGS) pump, semi-closed loop insulin delivery system, sensor-augmented pump therapy with the low-glucose suspend feature, threshold-based insulin pump interruption

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that causes pancreatic beta cell destruction, absolute insulin deficiency, and the need for exogenous insulin therapy.1 Patients with T1DM may administer multiple daily injections (MDIs) of insulin using a needle and syringe or insulin pen, or they wear an external insulin pump that delivers basal and bolus insulin at user-selectable rates through an infusion set inserted into the subcutaneous tissue. Upon diagnosis, patients with T1DM undergo multidisciplinary evaluation to discuss insulin delivery options, glucose monitoring options, and glycemic control challenges and to establish a treatment plan (i.e., target blood glucose levels, glycated hemoglobin HbA1c goals). The HbA1c test measures the average amount of glucose in blood over a two- to three-month period. Clinicians encourage most patients with T1DM to intensively manage their diabetes by maintaining an HbA1c level of 7% (average blood glucose 154 mg/dl) or below, a value shown to be associated with fewer long-term diabetes-related complications (e.g., nephropathy, retinopathy, neuropathy, heart disease).1-3

People with T1DM typically use feedback from a blood glucose monitor to adjust insulin dosages as needed, based on physical activity and diet.4 Some also use a continuous glucose monitor (CGM), which measures glucose levels in real time throughout the day and night. Sensor-augmented pump therapy involves use of an integrated system consisting of an insulin pump and CGM that wirelessly transmits data to a receiver or to the pump. Some physicians have patients wear a three-day CGM periodically (e.g., every six months) for blinded collection of glucose data.5 In this case, patients do not see CGM data until after the healthcare professional analyzes the data. Despite these measures, many people with T1DM do not achieve their glycemic control goals, and intensive diabetes management puts them at increased risk for hypoglycemia (blood glucose <70 mg/dl). Hypoglycemic episodes "can contribute to glucose variability because of release of counter-regulatory hormones and overtreatment with glucose."6 Severe hypoglycemia can cause seizures, coma, and in rare cases, death.7,8

Most individuals with T1DM can recognize the symptoms of a hypoglycemic event (i.e., shakiness, sweating, nervousness, tingling in the lips, confusion, irritability) and are able to self-administer an oral carbohydrate without needing medical attention.8 However, some feel no symptoms and are unaware of hypoglycemia.9 Decreased hypoglycemia awareness occurs more frequently in people who have had T1DM for a long time, who frequently have low blood-glucose episodes, and who intensively manage their disease.9-11 These individuals are at increased risk for severe hypoglycemia (glucose levels <50 mg/dl) because they are less likely to wake from sleep when hypoglycemia occurs during the night.9 Also, children with T1DM, in particular, are at high risk for adverse outcomes associated with hypoglycemia because of "the challenges presented by insulin dosing, variable eating patterns, erratic activity, and the limited ability of small children to detect hypoglycemia."12 Treating severe hypoglycemia often requires the assistance of another person to administer intravenous glucose or intramuscular glucagon.8

To optimize glucose management for people with T1DM, many experts believe "the best therapeutic option is an artificial pancreas device system (APDS) that can mimic normal pancreatic beta cell function thereby restoring normal metabolic homeostasis without causing hypoglycemia."7 An APDS is intended to provide a complete system, known as a closed-loop system, by combining several technologies: a glucose monitoring device, an external or implantable insulin pump, and advanced algorithm software designed to deliver appropriate doses of insulin from the insulin pump, based on the sensor glucose values.13 Developers of closed-loop systems face the following challenges:14-18

Fully automated APDSs are a few years away from availability, but systems incorporating some function of a fully automated APDS are commercially available. The first-generation step toward a fully automated APDS is a threshold-suspend insulin/LGS delivery system, which automatically shuts off insulin delivery when the blood glucose level drops below a preset threshold, indicating hypoglycemia.19 The only system of this type currently on the U.S. market is the MiniMed 530G with Enlite System (Medtronic, plc), which has been available since late 2013. Medtronic has also marketed a variation of this system, called the Paradigm Veo System, in Europe since 2009 (see Manufacturer, Regulatory, and Indications sections below). The MiniMed 530G with Enlite System is intended to reduce hypoglycemic excursions by automatically suspending insulin administration (for up to two hours) when a patient's glucose level drops below a preset level if the patient does not respond to the threshold-suspend alarm.20-22 Two clinical experts who provided comments to ECRI Institute on this technology estimate that 10% to 20% of patients with T1DM in their practices may be candidates for threshold-suspend insulin delivery to manage hypoglycemia.23,24

According to the American Diabetes Association, T1DM accounts for about 5% of all diagnosed cases of diabetes mellitus (about 1.1 million cases).25 According to one clinical expert who provided comments to ECRI Institute on this technology, "about 20% to 25% of patients with T1DM have decreased awareness (no symptoms at a blood sugar of 60mg/dl to 70mg/dl but some symptoms at a blood sugar <60mg/dl) and about 10% to 15% of patients with T1DM have severe decreased hypoglycemia awareness (no symptoms at a blood sugar <50mg/dl)."23

Our searches identified the following relevant statistics on severe hypoglycemia...