Draft Policies - Medicine
Intermittent Intravenous Insulin Therapy
Comment Period Ends:09-01-2018
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Intermittent intravenous insulin therapy, also known by other names, including but not limited to pulsatile intravenous insulin therapy (PIVIT), pulse insulin therapy, chronic intermittent intravenous insulin therapy (CIIIT), outpatient intravenous insulin treatment/therapy (OIVIT), hepatic activation therapy, metabolic activation therapy, and Trina Health®’s Artificial Pancreas Treatment®/Microburst Insulin® infusion, is considered experimental, investigational and/or unproven for all indications.
NOTE: This policy does not apply to use of intravenous insulin infusions in the inpatient setting (i.e., for the treatment of diabetic ketoacidosis or diabetic hyperosmolar coma).
Insulin-mediated glucose homeostasis involves 3 primary functions that occur at 3 locations: (1) insulin secretion by the pancreas; (2) glucose uptake, primarily in the muscle, liver, gut, and fat; and (3) hepatic glucose production. In the fasting state, when insulin levels are low, most glucose uptake into cells is non-insulin-mediated. Glucose uptake is then balanced by the liver production of glucose. However, after a glucose challenge, insulin binds to specific receptors on the hepatocyte to suppress glucose production. Without this inhibition, marked hyperglycemia may result.
Medications for Glucose Homeostasis in Diabetes
Diabetes is characterized by elevated blood glucose levels due to inadequate or absent insulin production (type 1 diabetes) or due to increased hepatic glucose production, decreased peripheral glucose uptake, and decreased insulin secretion (type 2 diabetes).
The different classes of diabetic drug therapy target different aspects of glucose metabolism. Various insulin secretagogues (e.g., sulfonylureas) function by increasing the pancreatic secretion of insulin; thiazolidinediones (e.g., pioglitazone [Actos], rosiglitazone [Avandia]) function in part by increasing glucose uptake in the peripheral (principally skeletal) tissues; and biguanides (e.g., metformin) function by decreasing hepatic glucose production. While patients with type 2 diabetes may be treated with various combinations of all three of these classes of drugs, with or without additional insulin, patients with type 1 diabetes, who have no baseline insulin secretion, receive exogenous insulin therapy. Standard insulin management involves the use of subcutaneous injection to mimic a physiologic insulin profile. Intravenous insulin is used in the acute inpatient setting to manage hyperglycemic emergencies (e.g., diabetic ketoacidosis).
Intermittent Insulin Therapy
Several forms of intermittent insulin therapy, in which insulin is delivered intravenously or into the peritoneal space, have been evaluated.
Intermittent intravenous insulin therapy— also known by other names, including but not limited to pulsatile intravenous insulin therapy (PIVIT), pulse insulin therapy, chronic intermittent intravenous insulin therapy (CIIIT), outpatient intravenous insulin treatment/therapy (OIVIT), hepatic activation therapy, metabolic activation therapy, and Trina Health®’s Artificial Pancreas Treatment®/Microburst Insulin® infusion — involves delivering insulin intravenously periodically over several hours in a pulsatile fashion using a specialized pump controlled by a computerized program.
Aoki et al. (1993) proposed that, in patients with type 1 diabetes, lower levels of insulin in the portal vein are associated with a decreased concentration of the liver enzymes required for hepatic metabolism of glucose. (1) They stated: “We reasoned that if the liver of an IDDM [insulin-dependent diabetes mellitus; i.e., type 1 diabetes] patient could be perfused with near-normal concentrations of insulin during meals, the organ could be reactivated,” and proposed that intermittent intravenous pulsatile infusions of insulin administered once weekly while the patient ingests a carbohydrate meal would increase the portal vein concentrations of insulin, ultimately stimulating the synthesis of glucokinase and other insulin-dependent enzymes. The pulses are designed to deliver a higher, more physiologic concentration of insulin to the liver than is delivered by traditional subcutaneous injections. This higher level of insulin is thought to more closely mimic the body’s natural levels of insulin because it is delivered to the liver. The goal of this outpatient therapy is improved glucose control through improved hepatic activation.
This policy was originally created in 2005 and has been updated regularly with searches of the MEDLINE database. The most recent literature review is through February 13, 2018.
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function - including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.
Aoki et al. (1993) published a case series of 20 patients with “brittle” type 1 diabetes. (1) All patients received 4 daily injections of insulin (type of insulin not described); additional oral drug therapy, if any, was not described. Throughout the study, patients remained in close contact with the clinic (at least once a week), during which time appropriate adjustments in diet, insulin doses, and physical activity were made. While the study reported a decrease in the hemoglobin A1c (HbA1c) levels, the lack of a control group limits interpretation of the results. For example, the intense follow-up of the patients could have impacted results, regardless of any possible effects of the intermittent intravenous insulin therapy. (1, 2)
Aoki et al. (1995) also examined the effect of chronic intermittent intravenous insulin therapy (CIIIT) with hypertensive medications in 26 patients with type 1 diabetes and associated hypertension and nephropathy. (3) The 26 patients were randomized to a control group or a treatment group for 3 months and then crossed over for an additional 3 months. At baseline, all patients were being treated with 4 daily insulin injections and had achieved acceptable HbA1c levels of 7.4%. Patients also achieved acceptable baseline blood pressure control (<140/90 mm Hg) with a variety of medications (i.e., angiotensin-converting enzyme inhibitors, calcium channel blockers, loop diuretics, alpha-2 agonists). The study was randomized, but not blinded, in that sham CIIIT procedures were not performed. Therefore, those patients receiving CIIIT received more intense follow-up during this period. During the treatment phase, patients reported a significant decrease in dosage of antihypertensive medicines. No difference in glycemic control was noted. Because all patients had adequate blood pressure control at baseline, the clinical significance of the decrease in antihypertensive dosage requirement associated with CIIIT is uncertain.
Section Summary: Glycemic Control
One nonblinded RCT and a case series reporting on the effect of CIIIT on glycemic control in type 1 diabetes were identified. Both studies reported improvements: one in HbA1c levels compared with baseline, and the other in a dose of antihypertensive medication in the treatment group compared with control. However, the lack of a blinded control comparator group in the RCT limits the conclusions that can be drawn.
Reductions in Diabetic End-Organ Damage
Weinrauch et al. (2010) published an RCT of the effects of pulsatile insulin infusion therapy on progression of nephropathy and retinopathy in 65 subjects with type 1 diabetes. (4) Patients were randomized to standard therapy of 3 to 4 daily subcutaneous insulin injections (n=29; control group) or standard therapy plus weekly pulsatile insulin infusion therapy (n=36; treatment group). Baseline demographic characteristics were similar between the 2 groups, as were the age of onset, duration of diabetes, control of HbA1c levels, and renal function (average creatinine, 1.59 mg/dL; average creatinine clearance, 60.6 mL/min). Primary end points were a progression of diabetic retinopathy and nephropathy. There was no significant difference in progression of diabetic retinopathy. Progression was noted in 18.8% of 122 eyes adequately evaluated (17.9% of 67 treated eyes, 20.0% of 55 controls; p=0.39). On average, serum creatinine increased in both groups; the increase was smaller in the treatment group (0.09 mg/dL) than in the control group (0.39 mg/dL; p=0.035). While average creatinine clearance fell less in the treatment group (-5.1 mL/min), the difference vs standard therapy was not significant (-9.9 mL/min; p=0.30). Glycemic control did not vary significantly. The clinical significance of the difference in creatinine levels is uncertain.
Dailey et al. (2000) reported on a prospective, multicenter, controlled study evaluating the effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy. (5) They assessed 49 type 1 diabetes patients with nephropathy who were following the Diabetes Control and Complications Trial intensive therapy regimen. Of these, 26 were assigned to the control group, which continued intensive therapy, and 23 were assigned to the treatment group, which underwent weekly pulsatile intravenous insulin therapy plus intensive therapy. Both groups reported a significant decrease in HbA1c levels during the 18-month study period. Creatinine clearance declined in both groups as expected, but the rate of decline in the treatment group was significantly less than in the control group. The clinical significance of this finding is uncertain. Larger clinical trials that evaluate the end point of time to progression of renal failure are needed.
Section Summary: Reductions in Diabetic End-Organ Damage
Two controlled studies focusing on the efficacy of pulsatile intravenous insulin therapy for reducing diabetic end-organ complications were identified. Both reported significant improvements in intermediate measures of glycemic control in each group from pre- to postintervention, but did not consistently report differences in clinically meaningful outcomes from the beginning of the studies to the end. Similarly, there were no significant differences between treatment groups in the RCT.
Elliot et al. (2017) reported on the data from three observational retrospective studies with the use of microburst insulin infusion. (10) In the 3 studies, patients continued to receive their regular regimen of hypoglycemic medications. The studies reported on the use of microburst insulin therapy to improve carbohydrate metabolism (n=311), reduce painful diabetic neuropathy (n=412) and to reduce emergency department visits and hospital admissions in patients with 2 or more secondary complications of diabetes (the two-year study included 1,524 patients). The authors concluded that microburst insulin therapy represents a new advance in the treatment of diabetes and the complications of diabetes.
Summary of Evidence
For individuals who have type 1 diabetes who receive intermittent intravenous insulin therapy, the evidence includes 2 RCTs, and several uncontrolled studies. For individuals who have type 1 and type 2 diabetes, evidence includes three observational retrospective studies using microburst insulin infusion. Relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. A limited number of uncontrolled studies have suggested that intermittent intravenous insulin therapy might improve glycemic control. The 2 randomized trials have reported that intermittent intravenous insulin therapy might moderate the progression of nephropathy or retinopathy. However, the published studies were small and reported improvements on intermediate outcomes only (i.e., changes in laboratory values). The clinical significance of the differences reported in these trials is uncertain. Additionally, most published evidence appeared between 1993 and 2000 and, as a result, does not account for improvements in diabetes care. The evidence is insufficient to determine the effects of the technology on health outcomes.
Practice Guidelines and Position Statements
Clinical practice guidelines from professional associations, including the American Diabetes Association (2017) (6) and the American Association of Clinical Endocrinologists and American College of Endocrinology (2015), (7) have not included intermittent intravenous insulin therapy in guidelines for managing type 1 diabetes.
The American College of Physicians updated its Best Practice Advice in 2014 on inpatient glycemic control, which provided some recommendations on the use of intensive insulin therapy, including (8):
• “Best Practice Advice 1: Clinicians should target a blood glucose level of 7.8 to 11.1 mmol/L (140- 200 mg/dL) if insulin therapy is used in SICU [surgical intensive care unit]/MICU [medical intensive care unit] patients.”
• “Best Practice Advice 2: Clinicians should avoid targets less than 7.8 mmol/L (140 mg/dL) because harms are likely to increase with lower blood glucose targets.”
Ongoing and Unpublished Clinical Trials
A currently unpublished trial that might influence this review is listed in Table 1.
Table 1. Summary of Key Trials
Multicenter Trial to Evaluate the Effects of Intensive Bolus Intravenous Insulin Delivery on Metabolic Integrity in Type 1 and Type 2 Diabetics Who Despite Tight Control and Proper Diet Still Suffer From Metabolic Problems
Nov 2015 (unknown)
NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.
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The HCPCS G9147 is specific to outpatient intravenous insulin treatment (OIVIT).
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The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.
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1. Aoki TT, Benbarka MM, Okimura MC, et al. Long-term intermittent intravenous insulin therapy and type 1 diabetes mellitus. Lancet. Aug 28 1993; 342(8870):515-518. PMID 8102666
2. Aoki TT, Grecu EO, Arcangeli MA. Chronic intermittent intravenous insulin therapy corrects orthostatic hypotension of diabetes. Am J Med. Dec 1995; 99(6):683-684. PMID 7503093
3. Aoki TT, Grecu EO, Prendergast JJ, et al. Effect of chronic intermittent intravenous insulin therapy on antihypertensive medication requirements in IDDM subjects with hypertension and nephropathy. Diabetes Care. Sep 1995; 18(9):1260-1265. PMID 8612440
4. Weinrauch LA, Sun J, Gleason RE, et al. Pulsatile intermittent intravenous insulin therapy for attenuation of retinopathy and nephropathy in type 1 diabetes mellitus. Metabolism. Mar 1 2010; 59(10):1429-1434. PMID 20189608
5. Dailey GE, Boden GH, Creech RH, et al. Effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy. Metabolism. Nov 2000; 49(11):1491-1495. PMID 11092517
6. Marathe PH, Gao HX, Close KL. American Diabetes Association Standards of Medical Care in Diabetes 2017. J Diabetes. Apr 2017; 9(4):320-324. PMID 28070960
7. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocr Pract. Apr 2015; 21 Suppl 1:1-87. PMID 25869408
8. Qaseem A, Chou R, Humphrey LL, et al. Inpatient glycemic control: best practice advice from the Clinical Guidelines Committee of the American College of Physicians. Am J Med Qual. Mar-Apr 2014; 29(2):95-98. PMID 23709472
9. Centers for Medicaid & Medicare Services. National Coverage Determination (NCD) for Outpatient Intravenous Insulin Treatment (40.7). 2009. Available at: <https://www.cms.gov> (accessed January 16, 2018).
10. Elliott J, Zaias N, Escovar S, et al. (2017) Microburst Insulin Infusion: Results of Observational Studies – Carbohydrate Metabolism, Painful Diabetic Neuropathy, and Hospital/Emergency Department Utilization. J Diabetes Metab Disord Control, 4(4): 00118. Available at: <https://medcraveonline.com> (accessed February 13, 2018).
11. Chronic Intermittent Intravenous Insulin Therapy. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Manual (2018 February) Medicine 2.01.43
|Date||Reason TBD Document updated with literature review. Coverage has changed to the following: Intermittent intravenous insulin therapy, also known by other names, including but not limited to pulsatile intravenous insulin therapy (PIVIT), pulse insulin therapy, chronic intermittent intravenous insulin therapy (CIIIT), outpatient intravenous insulin treatment/therapy (OIVIT), hepatic activation therapy, metabolic activation therapy, and Trina Health®’s Artificial Pancreas Treatment®/Microburst Insulin® infusion is considered experimental, investigational and/or unproven for all indications. Title has changed from Chronic Intermittent Intravenous Insulin Therapy (CIIIT). Reference 10 added.|
|6/1/2017||Document updated with literature review. Coverage unchanged.|
|5/15/2016||Reviewed. No changes|
|8/15/2015||Document updated with literature review. Coverage unchanged.|
|9/15/2014||Reviewed. No changes.|
|6/15/2013||Document updated with literature review. Coverage unchanged.|
|8/1/2011||Document updated with literature review. Coverage unchanged. CPT/HCPCS codes added.|
|9/1/2007||Revised/Updated Entire Document|
|5/1/2005||New Medical Document|
|Title:||Effective Date:||End Date:|
|Intermittent Intravenous Insulin Therapy||12-15-2018||04-14-2019|
|Chronic Intermittent Intravenous Insulin Therapy (CIIIT)||06-01-2017||12-14-2018|
|Chronic Intermittent Intravenous Insulin Therapy (CIIIT)||05-15-2016||05-31-2017|
|Chronic Intermittent Intravenous Insulin Therapy (CIIIT)||08-15-2015||05-14-2016|
|Chronic Intermittent Intravenous Insulin Therapy (CIIIT)||09-15-2014||08-14-2015|
|Chronic Intermittent Intravenous Insulin Therapy (CIIIT)||06-15-2013||09-14-2014|
|Chronic Intermittent Intravenous Insulin Therapy (CIIIT)||08-01-2011||06-14-2013|
|Chronic Intermittent Intravenous Insulin Therapy (CIIIT)||09-01-2007||07-31-2011|
|Chronic Intermittent Intravenous Insulin Therapy (CIIIT)||05-01-2005||08-31-2007|