| Coverage Policy Manual | |
| Policy #: | 2001009 |
| Category: | Medicine |
| Initiated: | May 2001 |
| Last Review: | October 2023 |
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| Non-Implantable Insulin Infusion Devices, Hybrid Insulin Infusion Devices, and Continuous Glucose Monitoring Devices | |
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| Description: |
Insulin Pump
An insulin pump is a portable device that is used to deliver insulin. It is composed of a pump reservoir similar to that of an insulin cartridge, a battery–operated pump, and a computer chip that allows the user to control the exact amount of insulin being delivered. Typically, the syringe has a two to three day insulin capacity and is connected to an infusion set attached to a small needle or cannula which the individual inserts into the subcutaneous tissue. The pump delivers insulin two ways: in a continuous flow called a “basal rate” and in a quick burst (at mealtime) called a “bolus.” The purpose of the insulin pump is to provide an accurate, continuous, controlled delivery of insulin which can be regulated by the user to achieve intensive glucose control objectives and to prevent the metabolic complications of hypoglycemia, hyperglycemia, and diabetic ketoacidosis.
CGM
The advent of blood glucose monitors for use by patients in the home revolutionized the management of diabetes. Using fingersticks, patients can monitor their blood glucose levels both to determine the adequacy of hyperglycemia control and to evaluate hypoglycemic episodes. Tight glucose control, defined as a strategy involving frequent glucose checks and a target hemoglobin A1c (HbA1c) level in the range of 7%, is now considered the standard of care for diabetic patients. Randomized controlled trials assessing tight control have demonstrated benefits for patients with type 1 diabetes in decreasing microvascular complications. The impact of tight control on type 1 diabetes and macrovascular complications such as stroke or myocardial infarction is less certain. The Diabetes Control and Complications Trial demonstrated that a relative HbA1c level reduction of 10% is clinically meaningful and corresponds to approximately a 40% decrease in risk for progression of diabetic retinopathy and a 25% decrease in risk for progression of renal disease (Diabetes Control and Complications Research Group, 2002).
Due to an increase in turnover of red blood cells during pregnancy, HbA1c levels are slightly lower in women with a normal pregnancy compared with nonpregnant women. The target A1c in women with diabetes is also lower in pregnancy. The American Diabetes Association recommends that, if achievable without significant hypoglycemia, the A1c levels should range between 6.0% to 6.5%; an A1c level less than 6% may be optimal as the pregnancy progresses (ADA, 2018).
Tight glucose control requires multiple daily measurements of blood glucose (i.e., before meals and at bedtime), a commitment that some patients may find difficult to meet. The goal of tight glucose control has to be balanced with an associated risk of hypoglycemia. Hypoglycemia is known to be a risk in patients with type 1 diabetes. While patients with insulin-treated type 2 diabetes may also experience severe hypoglycemic episodes, there is a lower relative likelihood of severe hypoglycemia compared with patients who had type 1 diabetes (Pazos-Couselo, 2015; Gehlaut, 2015). An additional limitation of periodic self-measurements of blood glucose is that glucose levels are seen in isolation, and trends in glucose levels are undetected. For example, while a diabetic patient’s fasting blood glucose level might be within normal values, hyperglycemia might be undetected postprandially, leading to elevated HbA1c levels.
Measurements of glucose in the interstitial fluid have been developed as a technique to measure glucose values automatically throughout the day, producing data that show the trends in glucose levels. Although devices measure glucose in the interstitial fluid on a periodic rather than a continuous basis, this type of monitoring is referred to as continuous glucose monitoring (CGM).
Currently, CGM devices are of 2 designs; real-time CGM (rtCGM) provides real-time data on glucose level, glucose trends, direction, and rate of change and, intermittently viewed (iCGM) devices that show continuous glucose measurements retrospectively. These devices are also known as flash-glucose monitors (FGM).
Approved devices now include devices indicated for pediatric use and those with more advanced software, more frequent measurements of glucose levels, or more sophisticated alarm systems. Devices initially measured interstitial glucose every 5 to10 minutes and stored data for download and retrospective evaluation by a clinician. With currently available devices, the intervals at which interstitial glucose is measured range from every 1-2 minutes to 5 minutes, and most provide measurements in real-time directly to patients. While CGM potentially eliminates or decreases the number of required daily fingersticks, it should be noted that, according to the U.S. Food and Drug Administration (FDA) labeling, some marketed monitors are not intended as an alternative to traditional self-monitoring of blood glucose levels but rather as adjuncts to monitoring, supplying additional information on glucose trends not available from self-monitoring. The devices must be calibrated twice daily with blood glucose measurements from fingersticks and are less reliable when used after exercise or post-prandial. Devices may be used intermittently (i.e., for periods of 72 hours) or continuously (i.e., on a long-term basis).
Automated Insulin Delivery Systems
As stated previously, tight glucose control in patients with diabetes has been associated with improved health outcomes. The American Diabetes Association has recommended a glycated hemoglobin level below 7% for most patients. However, hypoglycemia, may place a limit on the ability to achieve tighter glycemic control. Hypoglycemic events in adults range from mild to severe based on a number of factors including the glucose nadir, the presence of symptoms, and whether the episode can be self-treated or requires help for recovery. Children and adolescents represent a population of type 1 diabetics who have challenges in controlling hyperglycemia and avoiding hypoglycemia. Hypoglycemia is the most common acute complication of type 1 diabetes.
Type 1 diabetes is caused by the destruction of the pancreatic beta cells which produce insulin, and the necessary mainstay of treatment is insulin injections. Multiple studies have shown that intensive insulin treatment, aimed at tightly controlling blood glucose, reduces the risk of long-term complications of diabetes, such as retinopathy and renal disease. Optimal glycemic control, as assessed by glycated hemoglobin, and avoidance of hyper- and hypoglycemic excursions have been shown to prevent diabetes-related complications. Currently, insulin treatment strategies include either multiple daily insulin injections or continuous subcutaneous insulin infusion with an insulin pump.
The U.S. Food and Drug Administration (FDA) describes the basic design of an automated insulin delivery system (artificial pancreas device system) as a continuous glucose monitoring linked to an insulin pump with the capability to automatically stop, reduce, or increase insulin infusion based on specified thresholds of measured interstitial glucose (FDA, 2012).
The artificial pancreas device system components are designed to communicate with each other to automate the process of maintaining blood glucose concentrations at or near a specified range or target and to minimize the incidence and severity of hypoglycemic and hyperglycemic events. An artificial pancreas device system control algorithm is embedded in software in an external processor or controller that receives information from the continuous glucose monitoring and performs a series of mathematical calculations. Based on these calculations, the controller sends dosing instructions to the infusion pump.
Different automated insulin device system types are currently available for clinical use. Sensor augmented pump therapy with low glucose suspend (suspend on low) may reduce the likelihood or severity of a hypoglycemic event by suspending insulin delivery temporarily when the sensor value reaches (reactive) a predetermined lower threshold of measured interstitial glucose. Low glucose suspension automatically suspends basal insulin delivery for up to 2 hours in response to sensor-detected hypoglycemia.
A sensor augmented pump therapy with predictive low glucose management (suspend before low) suspends basal insulin infusion with the prediction of hypoglycemia. Basal insulin infusion is suspended when sensor glucose is at or within 70 mg/dL above the patient-set low limit and is predicted to be 20 mg/dL above this low limit in 30 minutes. In the absence of a patient response, the insulin infusion resumes after a maximum suspend period of 2 hours. In certain circumstances, auto-resumption parameters may be used.
When a sensor value is above or predicted to remain above the threshold, the infusion pump will not take any action based on continuous glucose monitoring readings. Patients using this system still need to monitor their blood glucose concentration, set appropriate basal rates for their insulin pump, and give premeal bolus insulin to control their glucose levels.
A control-to-range system reduces the likelihood or severity of a hypoglycemic or hyperglycemic event by adjusting insulin dosing only if a person's glucose levels reach or approach predetermined higher and lower thresholds. When a patient's glucose concentration is within the specified range, the infusion pump will not take any action based upon continuous glucose monitoring readings. Patients using this system still need to monitor their blood glucose concentration, set appropriate basal rates for their insulin pump, and give premeal bolus insulin to control their glucose levels.
A control-to-target system sets target glucose levels and tries to maintain these levels at all times. This system is fully automated and requires no interaction from the user (except for calibration of the continuous glucose monitoring). There are 2 subtypes of control-to-target systems: insulin-only and bihormonal (e.g., glucagon).
An artificial pancreas device system may also be referred to as a “closed-loop” system. A closed-loop system has automated insulin delivery and continuous glucose sensing and insulin delivery without patient intervention. The systems utilize a control algorithm that autonomously and continually increases and decreases the subcutaneous insulin delivery based on real-time sensor glucose levels.
A hybrid closed-loop system also uses automated insulin delivery with continuous basal insulin delivery adjustments. However, at mealtime, the patient enters the number of carbohydrates they are eating in order for the insulin pump to determine the bolus meal dose of insulin. A hybrid system option with the patient administration of a premeal or partial premeal insulin bolus can be used in either control-to-range or control-to-target systems.
Regulatory Status
External Insulin Pumps
Several external insulin pumps have been approved by the U.S. Food and Drug Administration (FDA) for the continuous infusion of insulin. Some examples include:
CGM
Multiple CGM systems have been approved by the FDA through the premarket approval process. FDA product codes: QCD, MDS
CGM devices labeled as “Pro” for specific professional use with customized software and transmission to health care professionals are not enumerated in this list. The Flash glucose monitors (e.g., FreeStyle Libre, Abbott) use intermittent scanning. The current version of the FreeStyle Libre device includes real-time alerts, in contrast to earlier versions without this feature.
Automated Insulin Delivery Systems
These systems are regulated by the FDA as class III device systems.
FDA-Approved Automated Insulin Delivery Systems:
The MiniMed 530G System includes a threshold suspend or low glucose suspend feature (FDA, 2013). The threshold suspend tool temporarily suspends insulin delivery when the sensor glucose level is at or below a preset threshold within the 60- to 90-mg/dL range. When the glucose value reaches this threshold, an alarm sounds. If patients respond to the alarm, they can choose to continue or cancel the insulin suspend feature. If patients fail to respond, the pump automatically suspends action for 2 hours, and then insulin therapy resumes.
The MiniMed® 630G System with SmartGuard™, which is similar to the 530G, includes updates to the system components including waterproofing (FDA, 2016). The threshold suspend feature can be programmed to temporarily suspend delivery of insulin for up to 2 hours when the sensor glucose value falls below a predefined threshold value. The MiniMed 630G System with SmartGuard™ is not intended to be used directly for making therapy adjustments, but rather to provide an indication of when a finger stick may be required. All therapy adjustments should be based on measurements obtained using a home glucose monitor and not on the values provided by the MiniMed 630G system. The device is not intended to be used directly for preventing or treating hypoglycemia but to suspend insulin delivery when the user is unable to respond to the SmartGuard™ Suspend on Low alarm to take measures to prevent or treat hypoglycemia themselves.
The MiniMed® 670G System is a hybrid closed-loop insulin delivery system consisting of an insulin pump, a glucose meter, and a transmitter, linked by a proprietary algorithm and the SmartGuard Hybrid Closed Loop (FDA, 2016). The system includes a low glucose suspend feature that suspends insulin delivery; this feature either suspends delivery on low-glucose levels or suspends delivery before low-glucose levels, and has an optional alarm (manual mode). Additionally, the system allows semiautomatic basal insulin-level adjustment (decrease or increase) to preset targets (automatic mode). As a hybrid system; basal insulin levels are automatically adjusted, but the patient needs to administer premeal insulin boluses. The continuous glucose monitoring component of the MiniMed 670G System is not intended to be used directly for making manual insulin therapy adjustments; rather it is to provide an indication of when a glucose measurement should be taken. The MiniMed 670G System was originally approved for marketing in the United States on September 28, 2016 (P160017) and received approval for marketing with a pediatric indication (ages 7-13 years) on June 21, 2018 (P160017/S031).
The MiniMed 770G System is an iteration of the MiniMed 670G System. In July 2020, the device was approved for use in children ages 2 to 6 years. In addition to the clinical studies that established the safety and effectiveness of the MiniMed 670G System in users ages 7 years and older, the sponsor performed clinical studies of the 670G System in pediatric subjects ages 2 to 6 years. FDA concluded that these studies establish a reasonable assurance of the safety and effectiveness of the MiniMed 770G System because the underlying therapy in the 670G system, and the associated Guardian Sensor (3), are identical to that of the 770G System (FDA, 2020).
On June 21, 2018, the FDA approved the t:slim X2 Insulin Pump with Basal-IQ Technology (PMA P180008) for individuals who are 6 years of age and older (FDA, 2018). The System consists of the t:slim X2 Insulin Pump paired with the Dexcom G5 Mobile Continuous Glucose Monitoring, as well as the Basal-IQ Technology. The t:slim X2 Insulin Pump is intended for the subcutaneous delivery of insulin, at set and variable rates, for the management of diabetes mellitus in persons requiring insulin. The t:slim X2 Insulin Pump can be used solely for continuous insulin delivery and as part of the System as the receiver for a therapeutic continuous glucose monitoring. The t:slim X2 Insulin Pump running the Basal-IQ Technology can be used to suspend insulin delivery based on continuous glucose monitoring sensor readings.
In December 2019, FDA approved the t:slim X2 Insulin Pump with Control-IQ Technology through the De Novo process (Faulds, 2019). The device uses the same pump hardware as the insulin pump component of the systems approved in t:slim X2 Insulin Pump with Basal-IQ Technology (P180008) and P140015. A custom disposable cartridge is motor-driven to deliver patient programmed basal rates and boluses through an infusion set into subcutaneous tissue
In 2022, FDA approved the Omnipod 5 ACE Pump for the subcutaneous delivery of insulin, at set and variable rates, for the management of diabetes mellitus in persons requiring insulin. The Omnipod 5 ACE Pump is able to reliably and securely communicate with compatible, digitally connected devices, including automated insulin dosing software, to receive, execute, and confirm commands from these devices.
In May 2023, FDA approved the first closed-loop system through the 510(k) premarket clearance pathway (FDA, 2023).
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Policy/ Coverage: |
Coverage policies 1998026 (Insulin Infusion Pumps, External) and 2001009 (Glucose Monitoring, Continuous) were combined into one policy (1998026 was archived January 2022). The updated policy was effective January 2022, and it includes Automated Insulin Delivery Systems.
Omnipod DASH and Omnipod 5 are not covered under the medical benefit. Please check the member’s pharmacy benefit for coverage.
Effective June 2023
I. External Insulin Pumps
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
A. Type 1 Diabetes Mellitus
1. External ambulatory insulin infusion pumps (Continuous ambulatory insulin infusion pump therapy [CSII]) meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when the following criteria are met and documented in the medical record for patients with:
OR
2. Automated Insulin Delivery Systems (open-loop or hybrid closed-loop automated insulin delivery system with a low glucose suspend feature) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with type 1 diabetes who meet ALL the following criteria:
OR
B. Type 2 Diabetes Mellitus
1. External ambulatory insulin infusion pumps (Continuous ambulatory insulin infusion pump therapy [CSII]) meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when the following criteria are met and documented in the medical record for patients with:
OR
C. In Pregnancy
1. External ambulatory insulin infusion pumps (Continuous ambulatory insulin infusion pump therapy [CSII]) meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in pregnant individuals with documented type 1 or type 2 diabetes who are insulin dependent AND has evidence of adequate diabetic education, dietary compliance, and motivation to follow an intensive insulin regimen.
Replacement Of External Insulin Infusion Pump
Replacement of an external insulin infusion pump meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when the above criteria have previously been met and ALL the following criteria is met:
Payments for insulin infusion pumps accrue to the annual DME limit.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of external insulin infusion pumps for any condition or circumstance other than those described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes, including but not limited to:
For members with contracts without primary coverage criteria, the use of external insulin infusion pumps for any condition or circumstance other than those described above is considered investigational, including but not limited:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Replacement of an external insulin infusion pump for any condition or circumstance other than those described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, replacement of an external insulin infusion pump for any condition or circumstance other than those described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Use of an open-loop or hybrid closed-loop automated insulin delivery system, including those with a low glucose suspend feature, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any condition or circumstance other than those described above.
For members with contracts without primary coverage criteria, use of an open-loop or hybrid closed- loop automated insulin delivery system, including those with a low glucose suspend feature, is considered investigational for any condition or circumstance other than those described above. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Replacement of a previously approved open-loop or hybrid closed-loop automated insulin delivery system with a low glucose suspend feature for any condition or circumstance other than those described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, replacement of a previously approved open-loop or hybrid closed-loop automated insulin delivery with a low glucose suspend feature for any condition or circumstance other than those described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
II. Continuous Glucose Monitors (CGM)
Meets Primary Coverage Criteria or Is Covered For Contracts Without Primary Coverage Criteria
Short-term CGM Device Monitoring
A. Type 1 or Type 2 Diabetes Mellitus
Brief (3 to 7 days), intermittent continuous monitoring of glucose in interstitial fluid meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
B. In Pregnancy
Brief (3 to 7 days), intermittent continuous monitoring of glucose in interstitial fluid meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
Long-term CGM Device Monitoring:
A. Type 1 or Type 2 Diabetes Mellitus
Long-term continuous monitoring of glucose in interstitial fluid, as a continuous monitoring technique to allow patients to self-manage their diabetes, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
B. In Pregnancy
Long-term continuous monitoring of glucose in interstitial fluid, as a continuous monitoring technique to allow patients to self-manage their diabetes, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
C. Existing External Insulin Pump
Long-term continuous monitoring of glucose in interstitial fluid, as a continuous monitoring technique to allow patients to self-manage their diabetes, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
Replacement Of Continuous Interstitial Glucose Monitoring Devices
Replacement of a continuous interstitial glucose monitoring device meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when the above criteria have previously been met and ALL the following criteria is met:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Continuous monitoring of glucose for any condition or circumstance other than those described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, continuous monitoring of glucose for any condition or circumstance other than those described above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of intermittently scanned (flash) CGM devices does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of intermittently scanned (flash) CGM devices is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Short-term and long-term CGM monitoring of glucose levels in interstitial fluid in individuals with type 2 diabetes not on intensive insulin therapy (i.e., individuals on basal insulin or oral antidiabetic agents only) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, short-term and long-term CGM monitoring of glucose levels in interstitial fluid in individuals with type 2 diabetes not on intensive insulin therapy (i.e., individuals on basal insulin or oral antidiabetic agents only) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of implantable CGM devices for management of type 1 or type 2 diabetes does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of implantable CGM devices for management of type 1 or type 2 diabetes is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Replacement of a continuous interstitial glucose monitoring device for any condition or circumstance other than those described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, replacement of a continuous interstitial glucose monitoring device for any condition or circumstance other than those described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective November 2022 to June 2023
1. External Insulin Pump
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
A.
External ambulatory insulin infusion pumps (Continuous ambulatory insulin infusion pump therapy [CSII]) meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when the following criteria are met and documented in the medical record:
AND
Meet one or more of the following criteria:
OR
B.
Pregnant individual with documented diabetes mellitus type 1 or type 2 diabetes mellitus who are insulin dependent AND has evidence of adequate diabetic education, dietary compliance, and motivation to follow an intensive insulin regimen.
Replacement Of External Insulin Infusion Pump
Replacement of an external insulin infusion pump meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when the above criteria have previously been met and ALL the following criteria is met:
Payments for insulin infusion pumps accrue to the annual DME limit.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of external insulin infusion pumps for any condition or circumstance other than those described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes, including but not limited to:
For members with contracts without primary coverage criteria, the use of external insulin infusion pumps for any condition or circumstance other than those described above is considered investigational, including but not limited to:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Replacement of an external insulin infusion pump for any condition or circumstance other than those described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, replacement of an external insulin infusion pump for any condition or circumstance other than those described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
2. Continuous Glucose Monitors (CGM)
Meets Primary Coverage Criteria or Is Covered For Contracts Without Primary Coverage Criteria
Short-term CGM Device Monitoring
Brief (3 to 7 days), intermittent continuous monitoring of glucose in interstitial fluid meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
OR
OR
Long-term CGM Device Monitoring:
Long-term continuous monitoring of glucose in interstitial fluid, as a continuous monitoring technique to allow patients to self-manage their diabetes, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
OR
OR
Provided ALL the following criteria are met:
Replacement Of Continuous Interstitial Glucose Monitoring Devices
Replacement of a continuous interstitial glucose monitoring device meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when the above criteria have previously been met and ALL the following criteria is met:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Continuous monitoring of glucose for any condition or circumstance other than those described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, continuous monitoring of glucose for any condition or circumstance other than those described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of intermittently scanned (flash) CGM devices does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of intermittently scanned (flash) CGM devices is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of adjunctive CGM devices does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of adjunctive CGM devices is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Short-term and long-term CGM monitoring of glucose levels in interstitial fluid in individuals with type 2 diabetes not on intensive insulin therapy (i.e., individuals on basal insulin or oral antidiabetic agents only) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, short-term and long-term CGM monitoring of glucose levels in interstitial fluid in individuals with type 2 diabetes not on intensive insulin therapy (i.e., individuals on basal insulin or oral antidiabetic agents only) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of implantable CGM devices for management of Type 1 and Type 2 diabetes mellitus does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, the use of implantable CGM devices for management of Type 1 and Type 2 diabetes mellitus is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Replacement of a continuous interstitial glucose monitoring device for any condition or circumstance other than those described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, replacement of a continuous interstitial glucose monitoring device for any condition or circumstance other than those described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
3. Automated Insulin Delivery Systems
Meets Primary Coverage Criteria or Is Covered For Contracts Without Primary Coverage Criteria
The use of an open-loop or hybrid closed-loop automated insulin delivery system with a low glucose suspend feature meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals who meet ALL the following criteria:
OR
Replacement Of An Open-Loop Or Hybrid Closed-Loop Automated Insulin Delivery System With A Low Glucose Suspend Feature
Replacement of an open-loop or hybrid closed-loop automated insulin delivery system with a low glucose suspend feature meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when the above criteria have previously been met and ALL the following criteria is met:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Use of an open-loop or hybrid closed-loop automated insulin delivery system, including those with a low glucose suspend feature, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any condition or circumstance other than those described above.
For members with contracts without primary coverage criteria, use of an open-loop or hybrid closed-loop automated insulin delivery system, including those with a low glucose suspend feature, is considered investigational for any condition or circumstance other than those described above. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Replacement of a previously approved open-loop or hybrid closed-loop automated insulin delivery system with a low glucose suspend feature for any condition or circumstance other than those described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, replacement of a previously approved open-loop or hybrid closed-loop automated insulin delivery with a low glucose suspend feature for any condition or circumstance other than those described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Due to the length of this policy, for dates of service prior to November 2022, the entire coverage history is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
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| Rationale: |
“Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com”
This policy was created in August 2021 as the result of combining the coverage policy for External Insulin Infusion Pumps (1998026), the coverage policy for Continuous Glucose Monitoring (2001009), and development for Automated Insulin Delivery System.
Diabetes is a condition that impairs the body’s ability to process blood glucose. According to the American Diabetes Association (ADA), in 2018, 34.2 million people in the United States (10.5% of the population) had a diagnosis of diabetes (ADA, 2021). Approximately 1.5 million Americans are diagnosed each year.
There are three major types of diabetes:
Diabetes can result in a number of long-term complications such as cardiovascular disease, neuropathy, nephropathy, retinopathy, skin conditions, hearing impairment, Alzheimer’s disease, and depression (Mayo Clinic, 2021). Blood glucose control helps decrease the risk of possible long-term complications.
External Insulin Infusion Pumps
The American Diabetes Association (ADA) Standards of Medical Care in Diabetes includes the following recommendations for insulin pumps (ADA, 2021):
Recommendations for Insulin Pumps
The Endocrine Society has the following recommendations (Peters, 2016):
Summary of Recommendations
AACE Insulin Pump Guidelines (Grunberger, 2018):
Type 1 Diabetes
Type 2 Diabetes
AACE Summary of Recommendations for Use of Advanced Technology in the Management of Persons with Diabetes Mellitus (Grunberger, 2021):
A review of 33 randomized, controlled trials in children and adults was conducted (Yeh, 2012). The reviews included a comparison of multiple daily injections (MDI) vs rapid-acting analogue–based continuous subcutaneous insulin infusion (CSII). The study concluded that CSII and MDI have similar effects on glycemic control and on hypoglycemia. However, CSII has a better effect on glycemic control on adults with type I diabetes.
The benefit of insulin pump use for individuals with type 2 diabetes was established by the results of the OpT2mise Study (Aronson, 2016; Conget, 2016). The OpT2mise study is a randomized controlled trial (RCT) that was designed to compare CSII and MDI in patients with type 2 diabetes. After 6 months, HgbA1C levels were reduced by significant amount with CSII as compared to MDI. Researchers concluded that an insulin pump can be a valuable treatment option for individuals with poorly controlled type 2 diabetes.
Continuous Glucose Monitoring
Continuous Glucose Monitoring Devices for Long-Term Use in Type 1 Diabetes
A number of systematic reviews and meta-analyses have assessed RCTs evaluating CGM for long-term, daily use in treating type 1 diabetes (Floyd, 2012; Gandhi, 2011; Langendam, 2012; Poolsup, 2013; Wojciechowski, 2011; Yeoh, 2015). These systematic reviews have focused on slightly different populations, and some did not separate long-term CGM from intermittent glucose monitoring (Poolsup, 2013). The only analysis to use individual patient data were published by Benkhadra et al (Benkhadra, 2017). The meta-analysis evaluated data from 11 RCTs that enrolled patients with type 1 diabetes and compared real-time CGM with a control intervention. Studies in which patients used insulin pumps or received multiple daily insulin injections were included. Reviewers contacted corresponding study authors requesting individual patient data; data were not obtained for 1 trial. Mean baseline HbA1c levels were 8.2% in adults and 8.3% in children and adolescents. The overall risk of bias in the studies was judged to be moderate. In pooled analyses, there was a statistically significantly greater decrease in HbA1c levels with real-time CGM vs control conditions. Overall, the degree of difference between groups was 0.26%. In subgroup analyses by age, there was a significantly greater change in HbA1c levels among individuals 15 years and older, but not among the younger age groups. There were no significant differences between groups in the time spent in hypoglycemia or the incidence of hypoglycemic events.
Earlier meta-analyses of glucose monitoring devices for type 1 diabetes tended to combine studies of intermittent glucose monitoring with studies of long-term CGM. Several reported separate subgroup analyses for long-term CGM. A Cochrane review by Langendam et al assessed CGM in type 1 diabetes in adults and children included RCTs; it compared CGM with conventional SMBG (Langendam, 2012). In pooled analysis (6 studies; n=963 patients) of studies of long-term CGM, the average decline in HbA1c levels 6 months after baseline was statistically significantly larger for CGM users than for SMBG users (mean difference [MD], -0.2%; 95% confidence interval [CI], -0.4% to -0.1%), but there was no difference in the decline in HbA1c levels at 12 months (1 study, n=154 patients; MD, 0.1%; 95% CI, -0.5% to 0.7%). In a meta-analysis of 4 RCTs (n=689 patients), there was no significant difference in the risk of severe hypoglycemia between CGM and SMBG users and the CI for the relative risk was wide (relative risk, 1.05; 95% CI, 0.63 to 1.77), indicating lack of precision in estimating the effect of CGM on hypoglycemia risk. Reviewers were unable to compare the longer-term changes in HbA1c levels or hypoglycemia outcomes for real-time CGM. Trials reporting results by compliance subgroups found larger treatment effects in highly compliant patients.
A systematic review by Wojciechowski et al (2011) evaluating CGM included RCTs conducted in adults and children with type 1 diabetes (Wojciechowski, 2011). Reviewers selected studies having a minimum of 12 weeks of follow-up and requiring patients to be on intensive insulin regimens. Studies compared CGM with SMBG; there was no restriction on the type of CGM device but CGM readings had to be used to adjust insulin dose or modify diet. Fourteen RCTs met the eligibility criteria. Study durations ranged from 3 to 6 months. Baseline mean HbA1c levels ranged from 6.4% to 10%. Five included studies found a statistically significant decrease in HbA1c levels favoring CGM, while 9 did not. In a pooled analysis, there was a statistically significant reduction in HbA1c levels with CGM compared with SMBG (weighted mean difference [WMD], -0.26%; 95% CI, -0.34% to -0.19%). For the subgroup of 7 studies that reported on long-term CGM, this difference was statistically significant (WMD = -0.26; 95% CI, -0.34 to -0.18). In a subgroup analysis by age, there were significant reductions in HbA1c levels with CGM in 5 studies of adults (WMD= -0.33; 95% CI, -0.46 to -0.20) and in 8 studies with children and/or adolescents (WMD= -0.25; 95% CI, -0.43 to -0.08). Four of the studies provided data on the frequency of hypoglycemic episodes. Pooled results showed a significant reduction in hypoglycemic events for CGM vs SMBG (standardized mean difference, -0.32; 95% CI, -0.52 to -0.13). In 5 studies reporting the percentage of patients with severe hypoglycemic episodes, there were no differences in the percentages of patients with severe hypoglycemic episodes using CGM and SMBG.
Recent RCTs not included in the meta-analyses above are described next. HbA1c, blood glucose, event rates, and patient reported outcomes were assessed at 6 months. None of the studies were blinded. The studies had a large number of pre-specified secondary endpoints, and analyses took into consideration the statistical impact of multiple comparisons.
Two, 2017 RCTs evaluated long-term CGM in patients with type 1 diabetes treated with multiple daily insulin injections. Both trials used the Dexcom G4 CGM device. Lind et al reported on a crossover study with 142 adults ages 18 and older who had baseline HbA1c levels of 7.5% or higher (mean baseline HbA1c level, »8.5%) (Lind, 2017). Enrolled patients underwent 26-week treatment periods with a CGM device and conventional therapy using SMBG, in random order. There was a 17-week washout period between intervention phases. The primary endpoint was the difference in HbA1c levels at the end of each treatment period. Mean HbA1c levels were 7.9% during CGM use and 8.4% during conventional therapy (MD = -0.4%; p<0.01). Treatment satisfaction (measured by the Diabetes Treatment Satisfaction Questionnaire) was significantly higher in the CGM phase than in the conventional treatment phase (p<0.001). There was 1 (0.7%) severe hypoglycemic event during the CGM phase and 5 (3.5%) events during conventional therapy. The percentage of time with hypoglycemia (<70 mmol/L) was 2.8% during CGM treatment and 4.8% during conventional therapy.
In the second study, Beck et al randomized 158 patients on a 2:1 basis to 24 weeks of CGM (n=105) or usual care (n=53) (Beck, 2017). The primary outcome (change in HbA1c levels at 24 weeks) was 1.0% in the CGM group and 0.4% in the usual care group (p<0.001), with a between-group difference of 0.6%. Prespecified secondary outcomes on the proportion of patients below a glycemic threshold at 24 weeks also favored the CGM group. The proportion of patients with HbA1c levels less than 7.0% was 18 (18%) in the CGM group and 2 (4%) in the control group (p=0.01). Prespecified secondary outcomes related to hypoglycemia also differed significantly between groups, favoring the CGM group. Comparable numbers for time spent at less than 50 mg/dL were 6 minutes per day in the CGM group and 20 minutes per day in the usual care group (p=0.001). The median change in the rate per 24 hours of hypoglycemia events lasting at least 20 minutes at less than 3.0 mmol/L (54 mg/dL) fell by 30% from 0.23 at baseline to 0.16 during follow-up in the CGM group but was practically unchanged (0.31 at baseline and 0.30 at follow-up) in the usual care group (p=0.03) (Riddlesworth, 2017). QOL measures assessing overall well-being (World Health Organization Well-Being Index), health status (EQ-5D-5L), diabetes distress (Diabetes Distress Scale), hypoglycemic fear (worry subscale of the Hypoglycemia Fear Survey), and hypoglycemic confidence (Hypoglycemic Confidence Scale) have also been reported (Polonsky, 2017). There were no significant differences between CGM and usual care in changes in well-being, health status, or hypoglycemic fear. The CGM group demonstrated a greater increase in hypoglycemic confidence (p=0.01) and a greater decrease in diabetes distress (p=0.01) than the usual care group.
The HypoDE study was a 6-month with 149 participants (Heinemann, 2018). 74 participants were placed in the control group, and 75 were assigned to the CGM group. 141 completed the follow-up phase (n=66 in the control group, n=75 in the CGM group). Results of the trial showed that CGM reduced the number of hypoglycemic events in individuals with type 1 diabetes who are treated by MDI and who have impaired hypoglycemia awareness or severe hypoglycemia. The mean number of hypoglycemic was reduced from 10·8 (SD 10·0) to 3·5 (4·7) in the CGM group, while the reductions among the control group were negligible (from 14·4 [12·4]to 13·7 [11·6]). The incidence of hypoglycemic events decreased by 72% for participants in the CGM group (incidence rate ratio 0·28 [95% CI 0·20-0·39], p<0·0001).
Two RCTs were published in 2020 that assessed CGM with a Dexcom G5 in adolescents and young adults, and in older adults (Laffel, 2020; Pratley, 2020). Both studies found modest but statistically significant differences in HbA1c between patients who used the CGM devices compared to the control arm at follow-up. Secondary measures of HbA1c and blood glucose were mostly better in the CGM arm. Patient-reported outcome measures were not significantly different between the groups, except that glucose monitoring satisfaction was higher in the adolescents and young adults who used CGM. With the newer technology, patients were able to use a smartphone app to monitor glucose levels.
One trial of real-time CGM in pregnant women with type 1 diabetes has been reported. Study characteristics, results, and gaps are summarized here. Feig et al reported results of 2 multicenter RCTs in women ages 18 to 40 with type 1 diabetes who were receiving intensive insulin therapy and who were either pregnant (≤13 weeks and 6 days of gestation) or planning a pregnancy (Feig, 2017). The trial enrolling pregnant women is reviewed here. Women were eligible if they had a singleton pregnancy and HbA1c levels between 6.5% and 10.0%. The trial was conducted at 31 hospitals in North America and Europe. Women were randomized to CGM (Guardian REAL-Time or MiniMed Minilink system) plus capillary glucose monitoring or capillary glucose monitoring alone. Women in the CGM group were instructed to use the devices daily. Women in the control group continued their usual method of capillary glucose monitoring. The target glucose range was 3.5 to 7.8 mmol/L and target HbA1c levels were 6.5% or less in both groups. The primary outcome was the difference in change in HbA1c levels from randomization to 34 weeks of gestation. The proportion of completed scheduled study visits was high in both groups; however, participants using CGM had more unscheduled contacts, which were attributed both to sensor issues and to sensor-related diabetes management issues. The median frequency of CGM use was 6.1 days per week (interquartile range, 4.0-6.8 d/wk) and 70% of pregnant participants used CGM for more than 75% of the time. The between-group difference in the change in HbA1c levels from baseline to 34 weeks of gestation was statistically significant favoring CGM (MD = -0.19%; 95% CI, -0.34 to -0.03; p=0.02). Women in the CGM group spent an increased percentage of time in the recommended glucose control target range at 34 weeks of gestation (68% vs 61%, p=0.003). There were no between-group differences in maternal hypoglycemia, gestational weight gain, or total daily insulin dose. A smaller proportion of infants of mothers in the CGM group were large-for-gestational-age (odds ratio [OR], 0.51; 95% CI, 0.28 to 0.90; p=0.02). In addition, for infants of mothers in the CGM group, there were fewer neonatal intensive care admissions lasting more than 24 hours (OR=0.48; 95% CI, 0.26 to 0.86; p=0.02), fewer incidences of neonatal hypoglycemia requiring treatment with intravenous dextrose (OR=0.45, 0.22 to 0.89; p=0.025), and reduced total hospital length stay (3.1 days vs 4.0 days; p=0.0091). Skin reactions occurred in 49 (48%) of 103 CGM participants and 8 (8%) of 104 control participants.
Continuous Glucose Monitoring Implanted Device for Long-Term Use
The Eversense Continuous Glucose Monitoring System is implanted in the subcutaneous skin layer and provides continuous glucose measurements over a 40-400 mg/dL range. The system provides real-time glucose values, glucose trends, and alerts for hypoglycemia and hyperglycemia and low glucose through a mobile application installed on a compatible mobile device platform. The Eversense CGM System is a prescription device indicated or use in adults (age 18 and older) with diabetes for up to 90 days. The device was initially approved as an adjunctive glucose monitoring device to complement information obtained from standard home blood glucose monitoring devices. Prescribing providers are required to participate in insertion and removal training certification.
Data from 3 nonrandomized prospective studies (PRECISE, PRECISE II, AND PRECISION) were provided to the FDA for the initial approval of Eversense as an adjunctive device (Kropff, 2017; Christiansen, 2018). Expanded approval was granted in June 2019 and Eversense is now approved as a device to replace fingerstick blood glucose measurements for diabetes treatment decisions (FDA, 2019). Historical data from the system can be interpreted to aid in providing therapy adjustments. The sponsor had previously performed clinical studies to establish the clinical measurement performance characteristics of the device, including accuracy across the claimed measuring range (40 to 400 mg/dL glucose), precision, claimed calibration frequency (every 12 hours), the wear period for the sensor (90 days), and performance of the alerts and notifications. This information was used to support what the FDA considered a reasonable assurance of safety and effectiveness of the device for the replacement of fingerstick blood glucose monitoring for diabetes treatment decisions. As a condition of approval, the sponsor was required to conduct a post-approval-study to evaluate the safety and effectiveness of diabetes management with the Eversense CGM System non-adjunctively compared to self-monitoring of blood glucose using a blood glucose meter in participants with either Type 1 or Type 2 diabetes (FDA, 2019).
Three post-marketing registry studies of the Eversense device have been published. Sanchez et al reported glucometric and safety data on the first 205 patients in the U.S. to use the Eversense device for at least 90 days (Sanchez, 2019). Of the 205 patients, 62.9% reported having T1D, 8.8% T2D, and 28.3% were unreported; results were not reported separately by diabetes type. Diess et al reported safety outcomes for 3,023 patients from 534 sites in Europe and South Africa who had used the device for 6 months or longer (Deiss, 2020). There were no serious adverse events, and the most commonly reported adverse events were sensor site infection and skin irritation. Tweden reported accuracy and safety data from 945 patients in Europe and South Africa who used either the 90-day or 180 day Eversense system for 4 insertion-removal cycles (Tweden, 2020). The percentage of patients using the 180-day system increased from cycle 1 to 4 as the device became more widely available (9%, 39%, 68% and 88% in cycles 1-4). There was no evidence of degradation of performance of the device over repeated insertion/removal cycles. Adverse events were not otherwise reported.
Numerous RCTs and several systematic reviews of RCTs have evaluated CGM in patients with type 1 diabetes. A 2017 individual patient data analysis, using data from 11 RCTs, found that reductions in HbA1c levels were significantly greater with real-time CGM compared with a control intervention. In addition, a 2012 meta-analysis of 6 RCTs found a significantly larger decline in HbA1c levels at 6 months in the CGM group than the SMBG group. There are few studies beyond 6 months. Two recent RCTs in patients who used multiple daily insulin injections and were highly compliant with CGM devices during run-in phases found that CGM was associated with a larger reduction in HbA1c levels than previous studies. Reductions were 0.4% and 0.6%, respectively, compared with approximately 0.2% to 0.3% in previous analyses. One of the 2 RCTs prespecified hypoglycemia-related outcomes and time spent in hypoglycemia were significantly lower in the CGM group.
One RCT in pregnant women with type 1 diabetes (n=215) has compared CGM with SMBG. Adherence was high in the CGM group. The difference in the change in HbA1c levels from baseline to 34 weeks of gestation was statistically significant favoring CGM, and women in the CGM group spent an increased percentage of time in the recommended glucose control target range at 34 weeks of gestation. There were no between-group differences in maternal hypoglycemia, gestational weight gain, or total daily insulin dose. A smaller proportion of infants of mothers in the CGM group were large for gestational age, had neonatal intensive care admissions lasting more than 24 hours, and had neonatal hypoglycemia requiring treatment. The total hospital length of stay was shorter by almost 1 day in the CGM group.
Three nonrandomized prospective studies and 3 postmarketing registry studies assessed the accuracy and safety of an implanted glucose monitoring system that provides continuous glucose monitoring for up to 4 insertion/removal cycles as an adjunct to home glucose monitoring devices. Accuracy measures included the mean absolute relative difference between paired samples from the implanted device and a reference standard blood glucose measurement. The accuracy tended to be lower in hypoglycemic ranges. Limitations on the evidence include lack of differentiation in outcomes type 1 diabetes vs type 2 diabetes and variability in reporting of trends in secondary glycemic measures. The initial approval of the device has been expanded to allow the device to be used for glucose management decision making. The same clinical study information was used to support what the FDA considered a reasonable assurance of safety and effectiveness of the device for the replacement of fingerstick blood glucose monitoring for diabetes treatment decisions. As a condition of approval, the sponsor is required to conduct an additional post-approval-study.
Continuous Glucose Monitoring Devices for Short-Term Use in Type 1 Diabetes
Meta-analyses of glucose monitoring devices for type 1 diabetes tend to combine studies of short-term glucose monitoring with studies of long-term CGM. For this body of evidence, there is variability in the definitions of intermittent monitoring and the specific monitoring protocols used. Also, many of the trials of short-term monitoring have included additional interventions to optimize glucose control (e.g., education, lifestyle modifications).
Two meta-analyses were identified that reported separate subgroup analyses for intermittent monitoring. In a Cochrane review by Langendam et al, 4 studies (total n=216 patients) compared real-time intermittent glucose monitoring systems with SMBG, and the pooled effect estimate for change in HbA1c levels at 3 months was not statistically significant (MD change, -0.18; 95% CI, -0.42 to 0.05) (Langendam, 2012). The meta-analysis by Wojciechowski et al, which assessed RCTs on CGM (described previously), also included a separate analysis of 8 RCTs of intermittent monitoring (Wojciechowski, 2011). On pooled analysis, there was a statistically significant reduction in HbA1c levels with intermittent glucose monitoring compared with SMBG (WMD= -0.26; 95% CI, -0.45 to -0.06).
The largest RCT was the Management of Insulin-Treated Diabetes Mellitus (MITRE) trial, published by Newman et al; it evaluated whether the use of the additional information provided by minimally invasive glucose monitors improved glucose control in patients with poorly controlled insulin-requiring diabetes (Newman, 2009). This 4-arm RCT was conducted at secondary care diabetes clinics in 4 hospitals in England. This trial enrolled 404 people over the age of 18 years, with insulin-treated diabetes (types 1 or 2) for at least 6 months, who were receiving 2 or more injections of insulin daily. Most (57%) participants had type 1 diabetes (41% had type 2 diabetes, 2% were classified as “other”). Participants had to have 2 HbA1c values of at least 7.5% in the 15 months before trial entry and were randomized to 1 of 4 groups. Two groups received minimally invasive glucose monitoring devices (GlucoWatch Biographer or MiniMed Continuous Glucose Monitoring System [CGMS]). Intermittent glucose monitoring was used (ie, monitoring was performed over several days at various points in the trial). These groups were compared with an attention control group (standard treatment with nurse feedback sessions at the same frequency as those in the device groups) and a standard control group (reflecting common practice in the clinical management of diabetes). Changes in HbA1c levels from baseline to 3, 6, 12, and 18 months were the primary indicator of short- to long-term efficacy. At 18 months, all groups demonstrated a decline in HbA1c levels from baseline. Mean percentage changes in HbA1c levels were -1.4% for the GlucoWatch group, -4.2% for the CGMS group, -5.1% for the attention control group, and -4.9% for the standard care control group. In the intention-to-treat analysis, no significant differences were found between any groups at any assessment times. There was no evidence that the additional information provided by the devices changed the number or nature of treatment recommendations offered by the nurses. Use and acceptability indicated a decline for both devices, which was most marked in the GlucoWatch group by 18 months (20% still using GlucoWatch vs 57% still using the CGMS). In this trial of unselected patients, glucose monitoring (CGMS on an intermittent basis) did not lead to improved clinical outcomes.
Voormolen et al published a systematic review of the literature on CGM during pregnancy (Voormolen, 2013). They identified 11 relevant studies (total n=534 women). Two were RCTs, one of which was the largest of the studies (n=154). Seven studies used CGMs that did not have data available in real-time; the remaining 4 studies used real-time CGM. Reviewers did not pool study findings; they concluded that the evidence was limited to the efficacy of CGM during pregnancy. The published RCTs are described next.
While both trials included a mix of women with type 1 and type 2 diabetes, most women had type 1 diabetes in both trials, so the trials are reviewed in this section.
Secher et al randomized 154 women with type 1 (n=123) and type 2 (n=31) diabetes to real-time CGM in addition to routine pregnancy care (n=79) or routine pregnancy care alone (n=75) (Secher, 2013). Patients in the CGM group were instructed to use the CGM device for 6 days before each of 5 study visits and were encouraged to use the devices continuously; 64% of participants used the devices per-protocol. Participants in both groups were instructed to perform 8 daily self-monitored plasma glucose measurements for 6 days before each visit. Baseline mean HbA1c levels were 6.6% in the CGM group and 6.8% in the routine care group. The 154 pregnancies resulted in 149 live births and 5 miscarriages. The prevalence of large-for-gestational-age infants (at least 90th percentile), the primary study outcome, was 45% in the CGM group and 34% in the routine care group. The difference between groups was not statistically significant (p=0.19). Also, no statistically significant differences were found between groups for secondary outcomes, including the prevalence of preterm delivery and the prevalence of severe neonatal hypoglycemia. Women in this trial had low baseline HbA1c levels, which might explain the lack of impact of CGM on outcomes. Other factors potentially contributing to the negative findings included the intensive SMBG routine in both groups and the relatively low compliance rate in the CGM group.
Murphy et al in the U.K. randomized 71 pregnant women with type 1 (n=46) and type 2 (n=25) diabetes to CGM or usual care (Murphy, 2008). The intervention consisted of up to 7 days of CGM at intervals of 4 to 6 weeks between 8 weeks and 32 weeks of gestation. Neither participants nor physicians had access to the measurements during sensor use; data were reviewed at study visits. In addition to CGM, the women were advised to measure blood glucose levels at least 7 times a day. Baseline HbA1c levels were 7.2% in the CGM group and 7.4% in the usual care group. The primary study outcome was maternal glycemic control during the second and third trimesters. Eighty percent of women in the CGM group wore the monitor at least once per trimester. Mean HbA1c levels were consistently lower in the intervention arm, but differences between groups were statistically significant only at week 36. For example, between 28 weeks and 32 weeks of gestation, mean HbA1c levels were 6.1% in the CGM group and 6.4% in the usual care group (p=0.10). The prevalence of large-for-gestational-age infants (at least 90th percentile) was a secondary outcome. Thirteen (35%) of 37 infants in the CGM group were large-for-gestational age compared with 18 (60%) of 30 in the usual care group. The odds for reduced risk of a large-for-gestational-age infant with CGM was 0.36 (95% CI, 0.13 to 0.98; p=0.05).
In summary, 2 trials of intermittent glucose monitoring conducted in Europe included pregnant women with type 1 or 2 diabetes, with most having type 1 diabetes. Secher et al included intermittent, real-time monitoring; Murphy et al included intermittent, retrospective monitoring with CGM (Secher, 2013; Murphy, 2008). The intervention started in early pregnancy in these studies; the mean age was in the early thirties and mean baseline HbA1c level was greater than 6.5%. There was no statistically significant difference between CGM and routine care for maternal HbA1c levels at 36 weeks in Secher et al; the difference in HbA1c levels at 36 weeks was about 0.6% (p=0.007) in Murphy et al. Secher et al also reported no difference in severe maternal hypoglycemia. The proportion of infants that were large for gestational age (>90th percentile) was higher in the CGM group in Secher et al although not statistically significantly higher; the difference in large for gestational age was statistically significantly lower for CGM in Murphy et al. The differences in the proportions of infants born via cesarean section, gestational age at delivery, and infants with severe hypoglycemia were not statistically significant in either trial.
For short-term monitoring of type 1 diabetes, there are few RCTs and systematic reviews. The evidence for short-term monitoring on glycemic control is mixed, and there was no consistency in HbA1c levels. Some trials have reported improvements in glucose control for the intermittent monitoring group but limitations in this body of evidence preclude conclusions. The definitions of control with short-term CGM use, duration of use and the specific monitoring protocols varied. In some studies, short-term monitoring was part of a larger strategy aimed at optimizing glucose control, and the impact of monitoring cannot be separated from the impact of other interventions. Studies have not shown an advantage for intermittent glucose monitoring in reducing severe hypoglycemia events but the number of events reported is generally small and effect estimates imprecise. The limited duration of use may preclude an assessment of any therapeutic effect. Two RCTs of short-term CGM use for monitoring in pregnancy included women with both type 1 and 2 diabetes, with most having type 1 diabetes. One trial reported a difference in HbA1c levels at 36 weeks; the proportion of infants that were large for gestational age (>90th percentile) favored CGM while the second trial did not. The differences in the proportions of infants born via cesarean section, gestational age at delivery, and infants with severe hypoglycemia were not statistically significant in either study. Limitations of the published evidence preclude determining the effects of the technology on net health outcome.
Continuous Glucose Monitoring Devices for Use in Type 2 Diabetes
The largest and most recent studies of CGM in adults with type 2 diabetes are briefly summarized in the following paragraphs. Baseline HbA1c levels were between 7.0% and 12.0% in the RCTs, with participants having a mean baseline age range in the mid-50s and early-60s. Most RCTs used a type of intermittent monitoring; some reported data for patients in real-time while others provided data reviewed only at study visits. No studies reported on follow-up beyond 12 months; thus the effect of CGM on outcomes related to diabetic complications is unknown.
An RCT, Multiple Daily Injections and Continuous Glucose Monitoring in Diabetes (DIAMOND), was reported by Beck et al (Beck, 2017). DIAMOND was performed at 25 endocrinology practices in North America (22 in the U.S., 3 in Canada) and enrolled adults with type 2 diabetes receiving multiple daily injections of insulin. One-hundred fifty-eight patients were randomized in 2 groups: CGM and usual care (n=79 in each group). Patients compliant during a run-in period were eligible for randomization. Patients in both groups were given a blood glucose meter. Participants in the CGM group were given a Dexcom G4 Platinum CGM System (Dexcom) and instructions on use. Change in HbA1c level from baseline to 24 weeks was the primary outcome. Analyses were adjusted for baseline HbA1c levels and the clinic was performed using intention-to-treat analysis with missing data handling by multiple imputations. At baseline, the mean total daily insulin dose was 1.1 U/kg/d. Week 24 follow-up was completed by 97% of the CGM group and 95% of the control group. Mean CGM use was greater than 6 d/wk at 1 month, 3 months, and 6 months. The adjusted difference in mean change in HbA1c level from baseline to 24 weeks was -0.3% (95% CI, -0.5% to 0.0%; p=0.022) favoring CGM. The adjusted difference in the proportion of patients with a relative reduction in HbA1c level of 10% or more was 22% (95% CI, 0% to 42%; p=0.028) favoring CGM. There were no events of severe hypoglycemia or diabetic ketoacidosis in either group. The treatment groups did not differ in any of the QOL measures.
Ehrhardt and colleagues published 2 reports from an RCT evaluating 100 patients (Vigersky, 2012; Ehrhardt, 2011). The trial evaluated the intermittent use of a CGM device in adults with type 2 diabetes treated with diet/exercise and/or glycemia-lowering medications but not prandial insulin who had an initial HbA1c level of at least 7% but not more than 12%. The trial compared real-time CGM with the Dexcom device used for 4, 2-week cycles (2 weeks on and 1 week off) with SMBG. The primary efficacy outcome was a mean change in HbA1c levels. Mean HbA1c levels in the CGM group were 8.4% at baseline, 7.4% at 12 weeks, 7.3% at 24 weeks, and 7.7% at 52 weeks. In the SMBG group, these values were 8.2% at baseline, 7.7% at 12 weeks, 7.6% at 24 weeks, and 7.9% at 52 weeks. During the trial, the reduction in HbA1c levels was significantly greater in the CGM group than in the SMBG group (p=0.04). After adjusting for potential confounders (eg, age, sex, baseline therapy, whether the individual started taking insulin during the study), the difference between groups over time remained statistically significant (p<0.001). The investigators also evaluated SMBG results for both groups. The mean proportions of SMBG tests less than 70 mg/dL were 3.6% in the CGM group and 2.5% in the SMBG group (p=0.06).
A systematic review of nineteen trials was conducted (Gandhi, 2011). CGM was associated with a significant reduction in mean hemoglobin A1c [HbA1c; weighted mean difference (WMD) of -0.27% (95% confidence interval [CI]-0.44 to -0.10)]. This was true for adults with T1DM as well as T2DM [WMD -0.50% (95% CI -0.69 to -0.30) and -0.70 (95% CI, -1.14 to -0.27), respectively]. Based on this review, continuous glucose monitoring seems to help improve glycemic control in adults with T1DM and T2DM. The study found that the effect on hypoglycemia incidence was imprecise and unclear. Larger trials with longer follow-up were recommended to assess the efficacy of CGM in reducing patient-important complications without significantly increasing the burden of care for patients with diabetes.
Flash glucose monitors use intermittent scanning; therefore, results are not reported in detail here. The sensor is inserted on the upper arm and, when held in close proximity, transmits the data to a separate reader device. The sensors allow high frequency monitoring of interstial fluid for up to 14 days. Haak et al reported the use of flash glucose-sensing technology as a replacement for SMBG for the management of insulin-dependent treated T2D and found no difference in HbA1c change at 6 months between groups (Haak, 2016; Haak, 2017). Intervention group participants did experience reductions in time in hypoglycemia compared with control for mild (<70mg/DL), moderate (<55mg/DL) and severe hypoglycemia (<45mg/dL) of 43%, 53% and, 64% respectively. Haak et al reported the results of a 12-month open-access extension of the REPLACE RCT comparing flash glucose-sensing technology in individuals with type 2 diabetes treated with intensive insulin therapy (Haak, 2017). Generally, the impact on outcomes of reduction in time in hypoglycemia and reduction in nocturnal hypoglycemia was maintained at 12 months. Furler et al reported on the use of the FreeStyle Libre Pro professional flash glucose monitor in the General Practice Optimizing Structured Monitoring to Improve Outcomes in Type 2 Diabetes (GP-OSMOTIC) trial (Furler, 2020). The pragmatic trial enrolled 299 patients across 25 sites in Australia. At 6 months patients randomized to the flash monitor had significantly lower HbA1c (–0·5%, 95% CI –0·8% to –0·3%; p=·0001), but there was no significant difference between groups at 12 months (–0·3%, 95% CI –0·5 to 0·01). The FreeStyle Libre Pro is not currently available in the United States.
As discussed in the section on CGM in pregnant women, 2 RCTs have evaluated short-term glucose monitoring in pregnant women with type 1 and type 2 diabetes. Most women had type 1 diabetes in both trials. There were 25 (35%) women with type 2 diabetes in Murphy et al and 31 (20%) with type 2 diabetes in Secher et al (Murphy, 2008; Secher, 2013). Results for women with type 2 diabetes were not reported in Murphy et al. Secher et al reported that 5 (17%) women with type 2 diabetes experienced 15 severe hypoglycemic events, with no difference between groups; other analyses were not stratified by diabetes type.
Only 2 RCTs used blinded CGM; in 1, there was no difference in reduction in HbA1c levels between CGM and control.
Most RCTs of CGM in patients with type 2 trials found statistically significant benefits of CGM regarding glycemic control. However, the degree of HbA1c reduction and the difference in HbA1c reduction between groups might not be clinically significant. Moreover, additional evidence would be needed to show what levels of improvements in HbA1c levels over the short-term would be linked to meaningful improvements over the long-term in health outcomes such as diabetes-related morbidity and complications. Also, the variability in entry criteria as well as among interventions makes it difficult to identify an optimal approach to CGM use; the studies used a combination of intermittent and continuous monitoring with a review of data in real-time or at study visits only. Only the DIAMOND trial (n=158) used real-time CGM in type 2 diabetes. Selected patients were highly compliant during a run-in phase. The difference in change in HbA1c levels from baseline to 24 weeks was -0.3% favoring CGM. The difference in the proportion of patients with a relative reduction in HbA1c level by 10% or more was 22% favoring CGM. There were no differences in the proportions of patients with an HbA1c level of less than 7% at week 24. There were no events of severe hypoglycemia or diabetic ketoacidosis in either group. The treatment groups did not differ in any of the QOL measures. Two trials of CGM have enrolled pregnant women with type 2 diabetes but the total number of women with type 2 diabetes included in both trials is only 58. One study reported a difference in HbA1c levels at 36 weeks, and the proportion of infants that were large for gestational age (>90th percentile) favored CGM while the second study did not. Neither trial reported analyses stratified by diabetes type.
Use of Long-Term (Continuous) CGM in Individuals with Type 2 Diabetes on Multiple Daily Doses of Insulin with Significant Hypoglycemia in the Setting of Insulin Deficiency
The largest and most recently published systematic review of RCTs reported a statistically significant reduction in hypoglycemic events in 285 subjects for CGM with a mean reduction of -0.35 (mean difference -0.59 to -0.10, p=0.0006) (Ida, 2019).
Twelve-month open-access, follow-up results for long-term CGM in 108 individuals with type 2 diabetes treated with intensive insulin therapy are summarized (Haak, 2017). Hypoglycemia was analyzed using 3 different glucose level thresholds (<70 mg/dl, <55 mg/dl, and <45 mg/dl). At all 3 glucose level thresholds, there were statistically significant reductions in time in hypoglycemia, frequency of hypoglycemic events, time in nocturnal hypoglycemia, and frequency of nocturnal hypoglycemia. Change for hypoglycemic events per day at 12 months compared to baseline was also significant: -40.8% (glucose <70 mg/dl, p<0.0001); -56.5% (glucose <55 mg/dl, p<0.0001); -61.7% (glucose <45 mg/dl, p=0.0001).
A recently published systematic review and 12-month follow-up study using long-term CGM in patients with type 2 diabetes demonstrate that CGM can significantly reduce time in hypoglycemia and frequency of hypoglycemia events both during the day and at night. At 12-month follow-up, hypoglycemic events were reduced by 40.8% to 61.7% with a greater relative reduction in the most severe thresholds of hypoglycemia. The published evidence supports a meaningful improvement in the net health outcome.
Continuous Glucose Monitoring Use in Pregnant Women With Gestational Diabetes
One trial of glucose monitoring in women with gestational diabetes has been published. In the RCT, Wei et al evaluated the use of CGM in 120 women with gestational diabetes at 24 to 28 weeks (Wei, 2016). Patients were randomized to prenatal care plus CGM (n=58) or SMBG (n=62). The CGM sensors were reportedly inserted for 48 to 72 hours on weekdays; it is not clear whether the readings were available in real-time. The investigators assessed a number of endpoints and did not specify primary outcomes; a significance level of p less than 0.05 was used for all outcomes. The groups did not differ significantly in a change in most outcomes, including a change in maternal HbA1c levels, rates of preterm delivery before the 35th gestational week, cesarean delivery rates, proportions of large-for-gestational-age infants, or rates of neonatal hypoglycemia. Women in the CGM group gained significantly less weight than those in the SMBG group.
The RCT in women with gestational diabetes was conducted in China with the intervention starting in the 2nd or 3rd trimester and mean baseline HbA1c level less than 6.0%. The type of CGM monitoring was unclear. Trial reporting was incomplete; however, there were no differences between groups for most reported outcomes.
Practice Guidelines and Position Statements
American Association of Clinical Endocrinologists and the American College of Endocrinology
In 2020, the AACE and the ACE 2015 Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan was supplemented by an AACE/ACE Consensus Statement on Comprehensive Type 2 Diabetes Management. It is recommended that therapy be evaluated regularly including the results of A1C, SMBG records (fasting and postprandial) or continuous glucose monitoring tracings. The statement supports consideration of the use of personal CGM devices for those patients who are on intensive insulin therapy (3 to 4 injections/day or on an insulin pump), for those with a history of hypoglycemia unawareness, or those with recurrent hypoglycemia. Regarding the duration of use the statement reads; “While these devices could be used intermittently in those who appear stable on their therapy, most patients will need to use this technology on a continual basis" (AACE and ACE, 2020).
National Institute for Health and Care Excellence
The National Institute for Health and Care Excellence updated its guidance on the diagnosis and management of type 1 diabetes in adults (NICE, 2016). The guidance stated that real-time CGM should not be offered “routinely to adults with type 1 diabetes” but that it can be considered in the following:
"...adults with type 1 diabetes who are willing to commit to using it at least 70% of the time and to calibrate it as needed, and who have any of the following despite optimized use of insulin therapy and conventional blood glucose monitoring:
American Diabetes Association
The American Diabetes Association “Standards of Medical Care in Diabetes: Diabetes Technology” included the following statement in the chapter on glycemic targets (ADA, 2020):
"Continuous glucose monitoring (CGM) also has an important role in assessing the effectiveness and safety of treatment in many patients with type 1 diabetes, and limited data suggest it may also be helpful in selected patients with type 2 diabetes, such as those on intensive insulin regimens."
The Standards also state that the technology has evolved rapidly in both accuracy and affordability and that data provided by CGM "will allow the provider to determine time in range (TIR) and to assess hypoglycemia, hyperglycemia, and glycemic variability", noting that there is a strong correlation between TIR and an A1C.
Endocrine Society
The Endocrine Society published clinical practice guidelines that included the following recommendations on CGM (Peters, 2016):
International Consensus on Time in Range
In 2019, consensus recommendations on clinical targets for CGM data interpretation were published and endorsed by the American Diabetes Association, American Association of Diabetes Educators, European Association for the Study of Diabetes, Foundation of European Nurses in Diabetes, International Society for Pediatric and Adolescent Diabetes, JDRF, and Pediatric Endocrine Society (Battelino, 2019).
Medicare National Coverage
In January 2017, the Centers for Medicare & Medicaid Services (CMS) ruled that CGM devices (therapeutic CGMs) approved by the U.S. Food and Drug Administration (FDA) that can be used to make treatment decisions are considered durable medical equipment (CMS, 2017). A CGM is considered a therapeutic CGM if it is approved by the FDA for use in place of a blood glucose monitor for making diabetes treatment decisions such as changes in diet and insulin dosage. Initially, CMS did not consider the smartphone application as a DME component and did allow payment for that part of the CGM system. Subsequently, in June 2018, CMS made an announcement that Medicare’s published coverage policy for CGMs will be modified to support the use of CGMs in conjunction with a smartphone, including the important data sharing function they provide for patients and their families (CMS, 2020).
Ongoing and Unpublished Clinical Trials
Ongoing Trials:
Unpublished Trials
Automated Insulin Delivery Systems
Low-Glucose Suspend Devices
A TEC Assessment reviewed studies that reported on the use of artificial pancreas device systems in patients with type 1 or type 2 diabetes taking insulin who were 16 years and older (BCBS TEC, 2013). It included studies that compared an artificial pancreas device system containing a low glucose suspend feature with the best alternative treatment in the above population, had at least 15 patients per arm, and reported on hypoglycemic episodes. A single trial met the inclusion criteria, and the TEC Assessment indicated that, although the trial results were generally favorable, the study was flawed and further research was needed. Reviewers concluded that there was insufficient evidence to draw conclusions about the impact of an artificial pancreas device system, with a low glucose suspend feature, on health outcomes.
The single trial assessed in the TEC Assessment was the in-home arm of the Automation to Simulate Pancreatic Insulin Response (ASPIRE) trial, reported by Bergenstal et al (Bergenstal, 2016). This industry-sponsored trial used the Paradigm Veo insulin pump. A total of 247 patients were randomized to an experimental group, in which a continuous glucose monitor with the low glucose suspend feature was used (n=121), or a control group, which used the continuous glucose monitor but not the low glucose suspend feature (n=126). Key eligibility criteria were 16-to-70 years old, type 1 diabetes, and HbA1clevels between 5.8% and 10.0%. In addition, patients had to have more than 6 months of experience with insulin pump therapy and at least 2 nocturnal hypoglycemic events (≤65 mg/dL) lasting more than 20 minutes during a 2-week run-in phase. The randomized intervention phase lasted 3 months. Patients in the low glucose suspend group were required to use the feature at least between 10 PM and 8 AM. The threshold value was initially set at 70 mg/dL and could be adjusted to between 70 mg/dL and 90 mg/dL. Seven patients withdrew early from the trial; all 247 were included in the intention-to-treat analysis. The primary efficacy outcome was the area under the curve (AUC) for nocturnal hypoglycemia events. This was calculated by multiplying the magnitude (in milligrams per deciliter) and duration (in minutes) of each qualified hypoglycemic event. The primary safety outcome was change in HbA1C levels.
The primary endpoint, mean (standard deviation [SD]) AUC for nocturnal hypoglycemic events, was 980 (1200) mg/dL/min in the low glucose suspend group and 1568 (1995) mg/dL/min in the control group. The difference between groups was statistically significant (p<0.001), favoring the intervention group.
Similarly, the mean AUC for combined daytime and nighttime hypoglycemic events (a secondary outcome) significantly favored the intervention group (p<0.001). Mean (SD) AUC values were 798 (965) mg/dL/min in the intervention group and 1,164 (1590) mg/dL/min in the control group. Moreover, the intervention group experienced fewer hypoglycemic episodes (mean, 3.3 per patient-week; SD=2.0) than the control group (mean, 4.7 per patient-week; SD=2.7; p<0.001). For patients in the low glucose suspend group, the mean number of times the feature was triggered per patient was 2.08 per 24-hour period and 0.77 each night (10PM-8AM). The median duration of nighttime threshold suspend events was 11.9 minutes; 43% of events lasted for less than 5 minutes, and 19.6% lasted more than 2 hours. In both groups, the mean sensor glucose value at the beginning of nocturnal events was 62.6 mg/dL. After 4 hours, the mean value was 162.3 mg/dL in the low glucose suspend group and 140.0 mg/dL in the control group.
Regarding safety outcomes and adverse events, change in HbA1c level was minimal, and there was no statistically significant difference between groups. Mean HbA1c levels decreased from 7.26 to 7.24 mg/dL in the low glucose suspend group and from 7.21 to 7.14 mg/dL in the control group. During the study period, there were no severe hypoglycemic events in the low glucose suspend group and 4 events in the control group (range of nadir glucose sensor values in these events, 40-76 mg/dL). There were no deaths or serious device-related adverse events.
Before reporting on in-home findings, the ASPIRE researchers published data from the in-clinic arm of the study (Forlenza, 2019). This randomized crossover trial included 50 patients with type 1 diabetes who had at least 3 months of experience with an insulin pump system. After a 2-week run-in period to verify and optimize basal rates, patients underwent 2 in-clinic exercise sessions to induce hypoglycemia. The low glucose suspend feature on the insulin pump was turned on in 1 session and off in the other session, in random order. When on, the low glucose suspend feature was set to suspend insulin delivery for 2 hours when levels reached 70 mg/dL or less. The goal of the study was to evaluate whether the severity and duration of hypoglycemia were reduced when the low glucose suspend feature was used. The study protocol called for patients to start exercise with glucose levels between 100 mg/dL and 140 mg/dL and to use a treadmill or stationary bicycle until their plasma glucose levels were 85 mg/dL or less. The study outcome (duration of hypoglycemia) was defined as the period of time glucose values were lower than 70 mg/dL and above 50 mg/dL, and hypoglycemia severity was defined as the lowest observed glucose value. A successful session was defined as an observation period of 3 to 4 hours and with glucose levels above 50 mg/dL. Patients who did not attain success could repeat the experiment up to 3 times.
The 50 patients attempted 134 exercise sessions; 98 of them were successful. Duration of hypoglycemia was significantly shorter during the low glucose suspend on sessions (mean, 138.5 minutes; SD=68) than the low glucose suspend off sessions (mean, 170.7 minutes; SD=91; p=0.006). Hypoglycemia severity was significantly reduced in the low glucose suspend on group. The mean (SD) lowest glucose level was 59.5 (72) mg/dL in the low glucose suspend on group and 57.6 (5.7) mg/dL in the low glucose suspend off group (p=0.015). Potential limitations of the Garg study included evaluation of the low glucose suspend feature in a research setting and short assessment period.
A second RCT evaluated the in-home use of the Paradigm Veo System (Ly, 2013). The trial by Ly et al in Australia was excluded from the 2013 TEC Assessment due to the inclusion of children and adults and lack of analyses stratified by age group (the artificial pancreas system approved in the United States at the time of the review was only intended for individuals ≥16 years). The Ly et trial included 95 patients with type 1 diabetes between 4 and 50 years of age (mean age, 18.6 years; >30% of sample <18 years old) who had used an insulin pump for at least 6 months. In addition, participants had to have an HbA1c level of 8.5% or less and have impaired awareness of hypoglycemia (defined as a score of at least 4 on the modified Clarke questionnaire). Patients were randomized to 6 months of in-home use of the Paradigm Veo System with automated insulin suspension when the glucose sensor reached a preset threshold of 60 mg/dL or to continued use of an insulin pump without the low glucose suspend feature. The primary study outcome was the combined incidence of severe hypoglycemic events (defined as hypoglycemic seizure or coma) and moderate hypoglycemic events (defined as an event requiring assistance from another person). As noted, findings were not reported separately for children and adults.
The baseline rate of severe and moderate hypoglycemia was significantly higher in the low glucose suspend group (129.6 events per 100 patient-months) than in the pump-only group (20.7 events per 100 patient-months). After 6 months of treatment, and controlling for the baseline hypoglycemia rate, the incidence rate per 100 patient-months was 34.2 (95% confidence interval [CI], 22.0 to 53.3) in the pump-only group and 9.6 (95% CI, 5.2 to 17.4) in the low glucose suspend group. The incidence rate ratio was 3.6 (95% CI, 1.7 to 7.5), which was statistically significant favoring the low glucose suspend group. Although results were not reported separately for children and adults, the trialists conducted a sensitivity analysis in patients younger than 12 years (15 patients in each treatment group). The high baseline hypoglycemia rates could be explained in part by 2 outliers (children ages 9 and 10 years). When both children were excluded from the analysis, the primary outcome was no longer statistically significant. The incidence rate ratio for moderate and severe events excluding the 2 children was 1.7 (95% CI, 0.7 to 4.3). Mean HbA1c levels (a secondary outcome) did not differ between groups at baseline or at 6 months. Change in HbA1c levels during the treatment period was -0.06% (95% CI, -0.2%to 0.09%) in the pump-only group and -0.1% (95% CI,-0.3% to 0.03%) in the low glucose suspend group; the difference between groups was not statistically significant.
The Predictive Low-Glucose Suspend for Reduction Of LOw Glucose (PROLOG) Trial was a 6-week crossover RCT of the t:slim X2 pump with Basal-IQ integrated with a Dexcom G5 sensor and a predictive low glucose suspe
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