Coverage Policy Manual
Policy #: 2005001
Category: Medicine
Initiated: January 2005
Last Review: August 2018
  Chronic Intermittent Intravenous Insulin Therapy (CIIIT)

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.
 
Background
There are 3 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 3 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 as outpatient intravenous insulin therapy (OIVIT), hepatic activation, or metabolic activation, 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.
 
Regulatory Status
Any 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.
 
Coding
 
There is no specific CPT code describing CIIIT.
 
In late 2009, a new HCPCS code was created specific to this therapy:
 
G9147: Outpatient intravenous insulin treatment (OIVIT) either pulsatile or continuous, by any means, guided by the results of measurements for: respiratory quotient, and/or, urine urea nitrogen (UUN), and/or, arterial, venous or capillary glucose, and/or potassium concentration.
  

Policy/
Coverage:
Effective, January 2005
Chronic intermittent intravenous insulin therapy is not covered  based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, chronic intermittent intravenous insulin therapy is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

Rationale:
This policy originated from an Arkansas Blue Cross Blue Shield Techology Evaluation done in October 2004.
 
There are 3 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 diabetics, marked hyperglycemia may result. Different classes of diabetic drug therapy target different aspects of glucose metabolism. Various insulin secretogogues (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 3 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 c) concentration of less than 7%.
 
CIIIT therapy is designed principally to normalize the hepatic metabolism of glucose. Although the exact physiologic mechanism is unclear, Aoki, one of the principal investigators of the technique, proposes 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.   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. In terms of clinical trials, because of the many variables associated with diabetic management, blinded randomized controlled clinical trials are necessary to validate treatment effectiveness; in fact, all of the drug therapies identified above have been the subject of a variety of clinical trials. 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.
 
Aoki also examined the effect of CIIIT on hypertension medications in 26 patients with type 1 diabetes and associated hypertension and nephropathy.   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., 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 followup 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. Aoki and colleagues examined the relationship between CIIIT and autonomic neuropathy.  This report consists of a case series of 3 patients and thus does not permit scientific conclusions.
 
Finally, Dailey and colleagues reported on the effect of CIIIT on the progression of diabetic nephropathy.  A total of 49 patients with type 1 diabetes were included. A total of 26 were assigned to the control group, while 23 were assigned to the treatment group who 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 looking at the endpoint of time to progression of renal failure are needed.
 
A January 2005 review of the peer-reviewed literature on MEDLINE found no clinical trials on CIIIT. Neither  the American Diabetes Association nor the American Association of Clinical Endocrinologists  include CIIIT within each organization's clinical practice guidelines for diabetes.
 
2007 Update
A Pubmed literature search revealed no clinical trials reporting chronic intermittent intravenous insulin therapy.
 
2009 Update
A search of the MEDLINE database was conducted through August 2009.  No new clinical trials on CIIIT were identified that would prompt a change in the coverage statement.  CIIIT is not included in the American Diabetes Association’s or the American Association of clinical Endocrinologists’ clinical practice guidelines for diabetes.  The policy statement remains unchanged.
 
2012 Update
This policy is updated with a search of the MEDLINE database through July 2012.  There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the relevant identified literature.
 
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 Weinrauch, 2010). 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.
 
Practice Guidelines and Position Statements
Clinical practice guidelines from professional associations, including the American Diabetes Association (ADA, 2009) and the American Association of Clinical Endocrinologists (Handelsman, 2011), do not include CIIIT within each organization’s clinical practice guidelines for diabetes.
 
Summary
A limited number of uncontrolled studies suggest that chronic intermittent intravenous insulin therapy (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.
 
2013 Update
A literature search conducted through July 2012 did not reveal any new evidence that would prompt a change in the coverage statement. A clinical practice guideline published by The American College of Physicians in 2011 on the use of intensive insulin therapy for the management of glycemic control in hospitalized patients (Qaseem, 2011) did not address outpatient chronic intermittent insulin therapy; the recommendations put forth in this guideline were based on earlier systematic review which did not include CIIT Kansagara, 2011).
 
2014 Update
A literature search conducted through July 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
2015 Update
A literature search conducted through July 2015 did not reveal any new information that would prompt a change in the coverage statement.  
 
2016 Update
A literature search conducted through June 2016 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through July 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update  
A literature search conducted through July 2018 did not reveal any new information that would prompt a change in the coverage statement.
   

CPT/HCPCS:
G9147Outpatient Intravenous Insulin Treatment (OIVIT) either pulsatile or continuous, by any means, guided by the results of measurements for: respiratory quotient; and/or, urine urea nitrogen (UUN); and/or, arterial, venous or capillary glucose; and/or potassium concentration

References: American Association of Clinical Endocrinologists.(2002) Medical Guidelines for the Management of Diabetes Mellitus: The AACE System of Intensive Diabetes Self-management-2002 Update. Endocr Pract 2002; 8(Suppl 1):40-65.

American Diabetes Association. Clinical Practice Recommendations 2009. Diabetes Care 2009; 32(suppl 1). Available online at: http://care.diabetesjournals.org/content/32/Supplement_1. Last accessed June 2012.

American Diabetes Association.(2004) Clinical Practice Recommendations 2004. Care 2004; 27(Suppl 1). Accessible at http-//care.diabetesiournals.org/content/vol27lsuppl 11 care.

Aoki TT, Benbarka MM, Okimura MC et al.(1993) Long-term intermittent intravenous insulin therapy and type 1 diabetes mellitus. Lancet 1993; 342(8870):515-8.

Aoki TT, Grecu EO, Arcangeli MA.(1995) Chronic intermittent intravenous insulin therapy corrects orthostatic hypotension of diabetes. Am J Mad 1995; 99(6):683-4.

Aoki TT, Grecu EO, Prendergast JJ et al.(1995) 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.

Chronic Intermittent Intravenous Insulin Therapy (CIIT) for Type 1 diabetes mellitus. Hayes Directory, 7/14/06.

Dailey GE, Boden GH, Creech RH et al.(2000) Effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy. Metabolism 2000; 49(11):1491-5.

Gill G, Wiliams G.(1993) Long-term intermittent intravenous therapy and type 1 diabetes mellitus. Lancet 1993; 342(8878):1056-8.

Handelsman Y, Bloomgarden ZT, Grunberger G, et al.(2015) American Association of Cinical 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

Handelsman Y, Mechanick JI, Blonde L et al.(2011) 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.

Kansagara D, Fu R, Freeman M et al.(2011) Intensive insulin therapy in hospitalized patients: a systematic review. Ann Intern Med 2011; 154(4):268-82.

Qaseem A, Chou R, Humphrey LL, et al.(2014) 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

Qaseem A, Humphrey LL, Chou R et al.(2011) Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2011; 154(4):260-7.

Weinrauch LA, Sun J, Gleason RE et al.(2010) Pulsatile intermittent intravenous insulin therapy for attenuation of retinopathy and nephropathy in type 1 diabetes mellitus. Metabolism 2010.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.