Standard Blood Glucose Monitoring 4x/Day as Prerequisite for Coverage of Continuous Glucose Monitor
Diabetes mellitus describes diseases of abnormal carbohydrate metabolism characterized by hyperglycemia that are associated with an absolute or relative impairment in insulin secretion, peripheral resistance to the action of insulin, or both. According to the CDC National Diabetes Statistics Report 2020, the estimated prevalence of diabetes in the US for 2018 was 34.2 million people or 10.5%, with 1.5 million Americans being diagnosed with diabetes every year.1 The percentage of adults with diabetes increases with age, reaching 26.8% (14.3 million) among those aged 65 years or older.1
CGM devices measure the glucose content of interstitial fluid every 1 to 15 minutes, depending on the device. Interstitial fluid is accessed by a sensor inserted subcutaneously by the patient and changed every 7 to 14 days. A transmitter is attached to the sensor or worn over the sensor and transmits the glucose data to a receiver/smartphone. CGM systems provide visualization of the current glucose value as well as trend analysis, which indicates the direction of changing glucose. This technology can help patients fine-tune diabetic treatment. There are two main types of CGM systems: real time CGM (RT-CGM) and devices that require intermittent scanning, also known as flash continuous glucose monitoring (FGM).
A therapeutic CGM is one that meets the definition of durable medical equipment (DME) and is labeled by the Food & Drug Administration (FDA) for non-adjunctive use (i.e., it can be used to make treatment decisions without the need for a stand-alone home blood glucose monitor to confirm testing results). Therapeutic CGM devices can be either RT-CGM or Flash CGM technology.
The aim of this summary of evidence was to determine if a self-monitoring blood glucose (SMBG) frequency requirement of ≥4x/day prior to initiating CGM is predictive of improved glycemic control, evidenced by a clinically significant improvement in HbA1c or reduction in rate of hypoglycemic events in type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) patients on intensive insulin regimens (multiple daily injections (MDI) ≥ 3/day or continuous subcutaneous infusion insulin (CSII)) compared to a lower frequency of SMBG testing.
Randomized Control Trials (RCTs) have demonstrated the efficacy of CGM or FGM use in individuals with T1DM2-10 and insulin-treated T2DM.2,8,11-13 Benefits of CGM include reduction in HbA1c,3,6,8,9,11,13 decreased time in hypoglycemic range and fewer total hypoglycemic events,4,5,7,10 and increased time in target glycemic range.2,8 Additionally, CGM use has been shown to be particularly effective among those with hypoglycemia unawareness and/or frequent episodes of severe hypoglycemia.4,5,10,12 In the studies that reported baseline SMBG frequencies there were no statistical differences noted between the intervention and control groups2-4,8,10-12 with the majority of studies reporting mean baseline SMBG frequencies of <4 times per day.2,3,8,11,12 Of the studies that required a minimum SMBG frequency as an inclusion criteria, there was considerable variability in this requirement (>10 times/week to ≥3 times/day). Notably, no studies required a minimum SMBG frequency of ≥4 times/day.4,8,10-12 In a pre-specified subgroup analysis of older adults (≥60 years) with T1DM or T2DM, >50% of both the intervention and control group participants reported SMBG frequencies of <4 times/day.8 Additionally, glycemic outcomes in CGM users were not stratified based on baseline SMBG frequency in any of the RCTs.
A long term non-randomized study (initial 52-week duration with additional 3-year follow-up) has also demonstrated that CGM provided significant and comparable decrease in HbA1c, glycemic variability, and incidence of hypoglycemia regardless of the insulin delivery system (CSII or MDI) compared to SMBG in patients with T1DM.14,15 A non-randomized study examining FGM in T1DM with structured therapeutic education was associated with improved HbA1c levels with a moderate increase in mild hypoglycemic events.16 These studies did not report baseline SMBG frequencies and did not require minimum SMBG frequencies as an inclusion criteria.
Systematic reviews with meta-analyses (SRMAs) attempted to examine the efficacy of CGM use in patients with T1DM17-20 and T2DM21-23 compared to SMBG. Several systematic reviews noted variability in observation periods, study populations, intervention type and mechanism of insulin delivery in the studies included, which posed some challenges in aggregating data. All SRMAs that reported on T1DM patients found that CGM use was associated with a significant reduction in HbA1c with mean differences (MD) between -0.25 to -6%. One SRMA noted a significant reduction in the number of hypoglycemic events20 and one noted a reduction in median exposure to hypoglycemia.18 The remainder of the SRMAs with results on T1DM reported no significant difference in the time spent in hypoglycemia.17,19 In the T2DM population, CGM was associated with a significant reduction in HbA1c levels;21-23 however, there was again variation in the presented aggregated data related to hypoglycemia; with one SRMA reporting a shorter time spent with hypoglycemia21 and one reporting insufficient data to determine results of this outcome.24 There was no mention in the SRMAs regarding the frequency of SMBG as a requirement for CGM eligibility or outcome data stratification based on the frequency of SMBG at baseline in the CGM intervention groups.
The ADA Clinical Standards state that most patients using intensive insulin regimens should be encouraged to assess glucose levels using SMBG and/or CGM prior to meals and snacks, at bedtime, prior to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycemic, and prior to and while performing critical tasks such as driving.25 No distinction is made in this Clinical Standard between T1DM and T2DM, and there is no discussion regarding the need for a prerequisite frequency of SMBG use prior to the initiation of CGM. Similarly, the CGM use guidelines of the AACE/ACE, the Endocrine Society, Diabetes Canada, and the Chinese Diabetes Society do not set a prerequisite minimum SMBG frequency.26-29 An outlier is the NICE guidance from the UK that sets a prerequisite SMBG frequency of at least 10 times/day if CGM is to be used to manage hyperglycemia (HbA1c of 9%); however, this recommendation appears to be based on cost; with the authors noting that based on their sensitivity analyses, SMBG 10 or 8 times remained the most cost effective strategy, while CGM was always more effective, but more costly.30
Use of Inhaled Insulin as Substitute for Insulin Injections
The DME MACs received a reconsideration request on 7/24/2020 from MannKind Corporation, manufacturer of Afrezza inhaled insulin, to change the language in the LCD: Glucose Monitors (L33822) to include use of inhaled insulin. MannKind stated that Medicare denials are occurring for patients using CGMs and inhaled insulin as an alternative to injected mealtime insulin. They requested a change in the criteria for CGM to include the following new added language (underlined):
- Has type 1 or type 2 diabetes;
- Currently uses a home blood glucose monitor (BGM) and performs at least four fingersticks per day;
- Takes insulin, either with inhalation, multiple daily injections (MDI) or an insulin pump;
- And has an insulin plan that requires frequent changes based on CGM readings.
Afrezza consists of single-use plastic cartridges filled with a white powder containing insulin (human), which is administered via oral inhalation using the disposable Afrezza Inhaler only. Patients self-administer inhaled insulin using a small dry-powder inhaler which contains a single-use cartridge, available in 4-, 8-, and 12-unit doses of insulin. Rapid-acting inhaled human insulin (Afrezza insulin human inhalation powder) is intended as an alternative to rapid-acting injectable insulin for prandial (mealtime) use by adults with T1DM or T2DM to improve glycemic control. The insulin is inhaled immediately before mealtime, as prescribed and as needed based on blood glucose measurements. Inhaled insulin must be used in combination with injectable long-acting insulin in patients with T1DM and in T2DM patients who require long-acting insulin. Compared with injected rapid-acting insulin, Afrezza has a faster onset of action (12 to 15 minutes) and shorter duration of action (approximately two hours), with a peak effect of 35 to 45 minutes due to rapid absorption from the lungs.31,32
The FDA approved the New Drug Application (NDA) for Afrezza on June 27, 2014.33 Afrezza is manufactured and marketed by MannKind; commercial distribution in U.S. pharmacies began in February 2015. Usage, warnings, and contraindications from Afrezza’s product labeling (FDA labeling) are as follows31:
- Afrezza is not a substitute for long-acting insulin, and patients with type 1 diabetes must use Afrezza with a long-acting insulin.
- Afrezza is not recommended for the treatment of diabetic ketoacidosis.
- Dosage adjustment may be needed when switching from another insulin to Afrezza.
- Afrezza is not recommended for use by patients who smoke or who have recently stopped smoking.
- Use of Afrezza is associated with a risk of acute bronchospasm in patients with chronic lung disease and has been observed in patients with asthma and COPD. Therefore, its use is contraindicated in patients with chronic lung disease, such as asthma or COPD.
- A detailed medical history, physical examination, and spirometry (FEV1) must be performed in all patients prior to use of Afrezza to identify potential lung disease.
- Afrezza causes a small decline in lung function (FEV1) over time. Pulmonary function should be assessed at baseline, after first six months of therapy, and annually thereafter, even in absence of pulmonary symptoms. In patients with a decline of ≥ 20% in FEV1 from baseline, consider discontinuing Afrezza. More frequent monitoring of pulmonary function in patients with symptoms such as wheezing, bronchospasm, breathing difficulties, or persistent/recurring cough should be considered. If symptoms persist, discontinue Afrezza.
Afrezza Prescribing Information contains a “black box” warning which states “WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE. See full prescribing information for complete boxed warning. Acute bronchospasm has been observed in patients with asthma and COPD using AFREZZA. AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD. Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients.” The FDA approved Afrezza with a Risk Evaluation and Mitigation Strategy (REMS), which required implementation of a communication strategy for healthcare providers who may prescribe Afrezza. The goal of the REMS is to mitigate the risk of acute bronchospasm associated with Afrezza by informing healthcare providers that34:
- There is risk of acute bronchospasm associated with Afrezza in patients with chronic lung disease.
- Acute bronchospasm has been observed with Afrezza in patients with asthma and COPD.
- Afrezza is contraindicated in patients with chronic lung disease.
- Patients must be evaluated for lung disease before starting on Afrezza.
Literature searches were conducted using the terms “inhaled insulin” and “Afrezza.” English-language studies on human patients published within the last 5 years were retrieved and reviewed, including a systematic review/meta-analysis and three RCTs, summarized here.
A 2015 systematic review and meta-analysis35 included 13 RCTs completed through May 2015 that compared mealtime Afrezza with placebo, oral antidiabetic drugs, or subcutaneous insulin in patients with T1DM or T2DM. Data from 12 trials (n=5,273, aged 18-80 years) were used for the meta-analysis and one four-year follow-up study was reviewed for long-term safety of Afrezza. Study endpoints were changes in HbA1c and body weight; safety outcomes, including severe hypoglycemia and pulmonary toxicity, were also evaluated. It should be noted that only four of the included studies had been published, with published data being used as the primary data source. Data sources for the remaining eight trials were clinicaltrials.gov or regulatory documentation. Two of these unpublished trials were pivotal, phase 3 RCTs36,37 subsequently published in 2015 that supported FDA approval of Afrezza and are described in more detail below.
In the 12 trials used in the meta-analysis, Afrezza reduced HbA1c by an average of 0.55% (95% CI: 0.34-0.78) from baseline. For patients with T1DM, decrease from baseline HbA1c was greater for subcutaneous insulin. In patients with T2DM who required insulin, there was no significant difference in HBA1c between Afrezza and subcutaneous insulin. For patients with T1DM or T2DM, use of Afrezza was associated with less weight gain than with subcutaneous insulin and fewer episodes of severe hypoglycemia (12% of Afrezza patients versus 19% of subcutaneous insulin patients). The most common reported pulmonary symptom was nonproductive cough, which was reported more frequently in patients taking Afrezza than those taking subcutaneous insulin or oral diabetes drugs (29% versus 4%). Cough was mild, occurred within 10 minutes of inhalation of Afrezza, and was not associated with changes in pulmonary function in studies of shorter duration. In the long-term safety study, 17% of patients reported cough at four-year follow-up. The authors concluded that Afrezza use should be limited to non-smoking adults with diabetes with no pulmonary disease who are unwilling or unable to use injectable insulin.35
Bode et al.36 was a 24-week, open-label, non-inferiority RCT that included adult patients with T1DM on basal insulin randomized to treatment with Afrezza (n=174) or insulin aspart (n=171) at mealtime. Afrezza was found to be noninferior to insulin aspart in reducing HbA1c, but reductions from baseline HbA1c were less with Afrezza (-0.21% vs -0.4%, respectively; 95% CI, 0.02 to 0.36, p). Afrezza was associated with less weight gain and fewer hypoglycemic episodes. Mild cough occurred in 31.6% of Afrezza patients, compared with 2.3% of insulin aspart patients, and led to discontinuation of Afrezza in 5.7%. The authors concluded that Afrezza is an option for mealtime insulin in T1DM in patients who have concerns about hypoglycemia or additional injections.36 A small RCT32 comparing mealtime Afrezza (n=26) with insulin aspart (n=34) published in 2018 reported similar results in patients with T1DM. Patients treated with Afrezza had longer times with in-range glucose with less time spent in hypoglycemic and less weight gain.
Rodenstock et al.37 was a 24-week, double-blind RCT that randomized adult patients with T2DM who were insulin-naïve and inadequately controlled on oral antidiabetic medication to receive Afrezza (n=177) or an inhaled placebo (n=176). Afrezza significantly reduced HbA1c (-0.82 vs -0.42 respectively; 95% CI, -0.57 to -0.23; p<0.0001); 38% of Afrezza patients achieved an HbA1c ≤7% compared with 19% of placebo patients (p=0.0005). Afrezza also effectively controlled postprandial hyperglycemia. Mild dry cough occurred similarly in both groups, suggesting that inactive ingredients in the inhaled powder, not insulin, cause the cough after inhalation. The authors concluded that Afrezza is an effective mealtime alternative to injected insulin in patients with T2DM who are inadequately controlled with oral hypoglycemic agents and resistant to adding injected insulin.37
According to Afrezza FDA product labeling, in the clinical studies used for regulatory approval, 381 patients were 65 years of age or older, with 20 of those aged 75 years or older. No overall differences in safety or effectiveness were observed between patients over 65 and younger patients.31
Professional Society Guidelines
Rapid-acting inhaled insulin is recommended as an alternative to rapid-acting insulin analogs when prandial insulin is required for patients with T1DM or T2DM by clinical guidelines. In the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan—2015, it states “When control of postprandial hyperglycemia (T2D) is needed, preference should be given to rapid-acting insulins (the analogs lispro, aspart, and glulisine or inhaled insulin) over regular human insulin because the former have a more rapid onset and offset of action and are associated with less hypoglycemia (Grade B; BEL 2).”27 They also note, “Physiologic insulin regimens, which provide both basal and prandial insulin, should be used for most patients with T1D (Grade A; BEL 1). These regimens involve the use of insulin analogs for most patients with T1D (Grade A; BEL 1) and include the following approaches: Multiple daily injections (MDI), which usually involve 1 to 2 subcutaneous injections daily of basal insulin to control glycemia between meals and overnight, and subcutaneous injections of prandial insulin or inhaled insulin before each meal to control meal-related glycemia (Grade A; BEL 1).”27
In its Standards of Medical Care in Diabetes—2020, the American Diabetes Association (ADA) includes rapid-acting inhaled insulin along with rapid-acting analogs when prandial insulin is required, noting that:
- “Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. Rapid-acting inhaled insulin to be used before meals is now available and may reduce rates of hypoglycemia in patients with type 1 diabetes.”38
- “More recently, two new insulin formulations with enhanced rapid action profiles have been introduced. Inhaled human insulin has a rapid peak and shortened duration of action compared with rapid-acting insulin and may cause less hypoglycemia and weight gain, and faster-acting insulin aspart may reduce prandial excursions better than rapid-acting insulin; further investigation is needed to establish a clear place for these agents in diabetes management.”38