BlueCross and BlueShield of Montana Medical Policy/Codes
Chronic Intermittent Intravenous Insulin Therapy (CIIIT)
Chapter: Medicine: Treatments
Current Effective Date: July 18, 2013
Original Effective Date: October 20, 2010
Publish Date: July 18, 2013
Revised Dates: November 06, 2012; April 8, 2013
Description

Chronic intermittent intravenous insulin therapy (CIIIT) is a technique for delivering variable-dosage insulin to diabetic patients with the goal of improved long-term glycemic control. Through an unknown mechanism, it is postulated to induce insulin-dependent hepatic enzymes to suppress glucose production. There are three main sites of insulin-mediated glucose homeostasis that must function in a coordinated fashion to maintain euglycemia: 1. insulin secretion by the pancreas; 2. glucose uptake, primarily in the muscle, liver, gut, and fat; and 3. hepatic glucose production. For example, in the fasting state, when insulin levels are low, the majority of glucose uptake is non-insulin mediated. Glucose uptake is then balanced by liver production of glucose, critical to nourish vital organs, such as the brain. However, after a glucose challenge, insulin binds to specific receptors on the hepatocyte to suppress glucose production. Without this inhibition, as can be seen in diabetic patients, marked hyperglycemia may result. Different classes of diabetic drug therapy target different aspects of glucose metabolism. Various insulin secretagogues (i.e., sulfonylureas) function by increasing the pancreatic secretion of insulin; thiazolidinediones (i.e., pioglitazone [Actos®]; and rosiglitazone [Avandia®]) function in part by increasing glucose uptake in the peripheral (principally skeletal) tissues; and biguanides (i.e., metformin) function by decreasing hepatic glucose production. While patients with type-2 diabetes may be treated with various combinations of all three of the above classes of drugs, patients with type-1 diabetes, who have no baseline insulin secretion, receive exogenous insulin therapy with or without additional drug therapy with thiazolidinediones or metformin. Large-scale randomized studies have established that tight glucose control is associated with a decreased incidence of microvascular complications of diabetes (i.e., nephropathy, neuropathy, and retinopathy). Currently, the American Diabetics Association recommends a target hemoglobin A1c (HbA1c) concentration of less than 7%.

Chronic intermittent intravenous insulin therapy (CIIIT) also referred to outpatient intravenous insulin therapy (OIVIT), hepatic activation, or metabolic activation, and/or pulsatile intravenous insulin therapy, involves delivering insulin intravenously over a 6- to 7-hour period in a pulsatile fashion using a specialized pump controlled by a computerized program that adjusts the dosages based on frequent blood glucose monitoring. 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 as they are delivered to the liver. It is hoped that this therapy ultimately results in improved glucose control through improved hepatic activation. CIIIT is typically delivered once weekly as outpatient therapy.

Any FDA approved insulin infusion pump can be used for the purposes of CIIIT. Infusion pumps have received U.S. Food and Drug Administration (FDA) marketing clearance through the 510(k) process, as they are determined to be substantially equivalent to predicate devices for the delivery of intravenous medications.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Chronic intermittent intravenous insulin therapy (CIIIT) is considered experimental, investigational and unproven.

Policy Guidelines

The HCPCS code G9147 is specific to CIIIT.  However, the following codes might be used to describe the various components of CIIIT, and some codes may be used more than once during a single session of CIIIT:  82948, 90765, 90766, 94681, 99070, 99211, J7050, J1817.

Rationale

This policy was originally created in 2010 and was regularly updated with searches of the MEDLINE database. This section of the current policy has been substantially revised. Following is a key summary of the literature to date:

Does CIIIT improve the hepatic metabolism of glucose?

Chronic intermittent intravenous insulin therapy (CIIIT) therapy is principally designed to normalize the hepatic metabolism of glucose. Although the exact physiologic mechanism is unclear, Aoki, one of the principal investigators of the technique, et al. proposed that in diabetic patients, 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) Once weekly 6-hour intravenous pulsatile infusions of insulin while the patient ingests a carbohydrate meal are designed to increase the portal vein concentrations of insulin, ultimately stimulating the synthesis of glucokinase and other insulin-dependent enzymes. No studies were identified in a MEDLINE literature search that investigated the proposed scientific mechanism of CIIIT in humans.

Does CIIIT improve glycemic control in diabetic patients?

Because of the many variables associated with diabetic management, randomized controlled clinical trials are necessary to validate treatment effectiveness. A MEDLINE literature search did not identify any blinded randomized clinical trials focusing on the efficacy of CIIIT for glucose control.

In 1993, Aoki and colleagues published a case series of 20 patients with “brittle” type 1 diabetes. All patients received 4 daily injections of insulin (type of insulin not described); any 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 appropriate adjustments in diet, insulin therapy, and activity were made. While the study reported a decrease in the HbA1c levels, the lack of a control group limits the interpretation of results. For example, the intense follow-up of the patients could have impacted results, regardless of any possible effects of the CIIIT. (1, 2)

Aoki et al. also examined the effect of CIIIT with hypertensive medications in 26 patients with type 1 diabetes and associated hypertension and nephropathy. (3) The 26 patients were randomly assigned to a control group or treatment group for 3 months and then crossed over to the opposite group 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 (below 140/90 mm Hg) with a variety of medications (i.e., angiotensin-converting enzyme [ACE] inhibitors, calcium channel blockers, loop diuretics, and alpha-2 agonists). While the study was randomized, it was 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. Since all patients had adequate blood pressure control at baseline, the clinical significance of the decrease in antihypertensive dosage requirement associated with CIIIT is uncertain.

Does CIIIT reduce diabetic end-organ damage?

Because of the many variables associated with diabetic management, randomized controlled clinical trials are necessary to validate treatment effectiveness. A MEDLINE literature search identified 2 randomized clinical trials focusing on the efficacy of CIIIT for reducing diabetic end-organ complications.

In 2000, Dailey and colleagues reported on the effect of CIIIT on the progression of diabetic nephropathy. (4) A total of 49 patients with type 1 diabetes were included. Of these, 26 were assigned to the control group, and 23 were assigned to the treatment group that underwent weekly CIIIT. Both groups reported a significant decrease in HbA1c during the 18-month study period. The creatinine clearance declined in both groups as expected, but the rate of decline in the treatment group was significantly less compared to the control group. Again, the clinical significance of this finding is uncertain; larger clinical trials that look at the endpoint of time to progression of renal failure are needed.

In 2010, Weinrauch and colleagues published a study of the effects of CIIIT on progression of nephropathy and retinopathy in 65 subjects with type I diabetes. (5) Patients were randomly allocated to standard therapy of 3-4 daily subcutaneous insulin injections (n=29) or standard therapy plus weekly CIIIT (n=36). Baseline demographic characteristics were similar between the 2 groups, as were age of onset, duration of diabetes, diabetic control and renal function (average creatinine 1.59 mg/dL, average creatinine clearance 60.6 mL/minute). Primary endpoints were 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 that were 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 less in the treatment group (0.09 mg/dL vs. 0.39 mg/dL, respectively; p=0.035). While average creatinine clearance fell less in the treatment group, the difference was not significant (-5.1 mL/minute vs. -9.9 mL/minute, respectively; p=0.30). Glycemic control did not vary significantly. The clinical significance of the difference in creatinine levels is unknown and requires further evaluation in trials involving a larger number of patients.

Ongoing Clinical Trials

A search of the online site ClinicalTrials.gov, in June 2012, found no clinical trials for this therapy. One related ongoing non-randomized, Phase III trial was identified. The “Effects of Intensive Bolus Intravenous Insulin Delivery on Metabolic Integrity in Type 1 and Type 2 Diabetes” trial is a multicenter trial to assess whether restoring metabolic integrity in 2,000 diabetic patients improves quality of life and complications associated with diabetes. (NCT01023165) This trial is expected to be completed in November 2015.

Summary

Chronic intermittent intravenous insulin therapy is a technique for delivering variable-dosage insulin to diabetic patients with the goal of improved long-term glycemic control. Through an unknown mechanism, it is postulated to induce insulin-dependent hepatic enzymes to suppress glucose production.

It is hypothesized that CIIIT improves hepatic glucose regulation. A limited number of uncontrolled studies suggest that CIIIT may improve glycemic control. Two randomized trials report that CIIIT may moderate the progression of nephropathy. However, the published studies are small and report benefits on intermediate outcomes only, i.e., changes in laboratory values. This evidence does not permit definitive conclusions regarding the health benefits of CIIIT. Therefore, the technique is considered experimental, investigational and unproven.

Practice Guidelines and Position Statements

Clinical practice guidelines from professional associations, including the American Diabetes Association and the American Association of Clinical Endocrinologists, do not include CIIIT within each organization’s clinical practice guidelines for diabetes. (6-8)

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

Experimental, investigational and unproven for all codes.

ICD-10 Codes

Experimental, investigational and unproven for all codes.

Procedural Codes: 82948, 94681, 96365, 96366, G9147, J1817, J7050
References
  1. Aoki TT, Benbarka MM, Okimura MC et al. Long-term intermittent intravenous insulin therapy and type 1 diabetes mellitus. Lancet 1993; 342(8870):515-8.
  2. Aoki TT, Grecu EO, Arcangeli MA. Chronic intermittent intravenous insulin therapy corrects orthostatic hypotension of diabetes. Am J Med 1995; 99(6):683-4.
  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 1995; 18(9):1260-5.
  4. Dailey GE, Boden GH, Creech RH et al. Effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy. Metabolism 2000; 49(11):1491-5.
  5. 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 (2010 Oct) 59(10):1429-34.
  6. Handelsman Y, Mechanick JI, Blonde L et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011; 17 Suppl 2:1-53.
  7. Rodbard HW, Blonde L, Braithwaite SS et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 2007; 13 Suppl 1:1-68.
  8. American Diabetes Association. Clinical Practice Recommendations 2009. Diabetes Care 2009; 32(suppl 1). Available online at: http://care.diabetesjournals.org .  Last accessed June 2012.
  9. Chronic Intermittent Intervenous Insulin Therapy. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Manual (2012 August) Medicine 2.01.43
History
April 2010  Medical Policy Physician's Committee (PAC) meeting approved. 
November 2012  Policy updated with literature search; policy statement unchanged.  References updated. 
April 2013 Policy language and formatting revised.  No change to policy statement. 
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Chronic Intermittent Intravenous Insulin Therapy (CIIIT)