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MP 2.01.43 Chronic Intermittent Intravenous Insulin Therapy (CIIIT)

Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature search/7:2013
  Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


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 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 [Actosâ] and rosiglitazone [Avandiaâ]) 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.


Chronic intermittent intravenous insulin therapy is considered investigational.

Policy Guidelines

There is no specific CPT code describing CIIIT. The following series of CPT codes and HCPCS J codes are used to describe the various components of CIIIT. Some codes, such as the code for glucose testing, may be used more than once during a single session of CIIIT:

CPT codes

82948: Glucose; blood reagent strip

94681: Oxygen uptake, expired gas analysis; including CO-2 output, percentage gas extracted

96365: Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to one hour

96366: ; each additional hour (List separately in addition to code for primary procedure)

99070: Supplies and materials provided by the physician

99211: Office or other outpatient visit

J codes

J7050: Infusion, normal saline solution, 250 cc

J1817: Insulin for administration through DME (i.e., insulin pump) per 50 units

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.

Benefit Application
BlueCard/National Account Issues

State or federal mandates (e.g., FEP) may dictate that all U.S. Food and Drug Administration (FDA)-approved devices, drugs, or biologics may not be considered investigational, and thus, these devices may be assessed only on the basis of their medical necessity.

Chronic intermittent intravenous insulin therapy is typically offered in specialized clinics. Locations offering CIIIT include: Sacramento, CA; Boca Raton and Fort Lauderdale, FL; Wichita, KS; Reno, NV; Brooklyn, NY; and Midland, TX. Further information can be found at the Aoki Diabetes Research Institute website, available online at:


Literature Review

This policy was originally created in 2001 and was regularly updated with searches of the MEDLINE database through June 7, 2013. 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); 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, in June 2013, 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. In addition, a pilot (Canadian single-center) randomized controlled trial is being conducted in 148 patients to determine whetherintermittent intensiveinsulin therapy is an effective therapeutic strategy that can preserve pancreatic beta-cell function and maintain glycemic control early in the course of type 2 diabetes. After a 3-week course of intensiveinsulin therapy, participants in the intervention arm will receiveintermittent intensive insulin therapy for one week every 3 months for the duration of the trial (24 months); participants in the control arm will be treated with ongoing metformin monotherapy. The primary outcome measure will be baseline-adjusted beta-cell function at 2 years, measured byInsulin Secretion-Sensitivity Index-2 (ISSI-2). This trial is not yet open for participant recruitment, and is expected to be completed in December 2017. (NCT01755468)


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.

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 investigational.

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, 7, 8) The American College of Physicians published a clinical practice guideline in 2011 on the use of intensive insulin therapy for the management of glycemic control in hospitalized patients(9); the recommendations put forth in this guideline were based on earlier systematic review on this topic which did not include CIIT. (10)

Medicare National Coverage

“Effective for claims with dates of service on and after December 23, 2009, the Centers for Medicare and Medicaid Services (CMS) determines that the evidence is adequate to conclude that outpatient intravenous insulin therapy (OIVIT, i.e., CIIIT) does not improve health outcomes in Medicare beneficiaries. Therefore, CMS determines that OIVIT is not reasonable and necessary for any indication under section 1862(a)(1)(A) of the Social Security Act. Services comprising an Outpatient Intravenous Insulin Therapy regimen are nationally non-covered under Medicare when furnished pursuant to an OIVIT regimen (see subsection A. above).”


  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; 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: Last accessed June 26, 2012.
  9. Qaseem A, Humphrey LL, Chou R et al. 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.
  10. Kansagara D, Fu R, Freeman M et al. Intensive insulin therapy in hospitalized patients: a systematic review. Ann Intern Med 2011; 154(4):268-82.




CPT    See Policy Guidelines
ICD-9 Procedure     
ICD-9 Diagnosis    Investigational for all relevant diagnoses
  216  Benign neoplasm of skin, code range 
HCPCS    See Policy Guidelines 
ICD-10-CM (effective 10/1/14)   Investigational for all relevant diagnoses
  E08.8-E13.9 Diabetes mellitus code range
ICD-10-PCS (effective 10/1/14)   ICD-10-PCS codes are only used for inpatient services. There are no specific ICD-10-PCS codes for this therapy.
  3E030VG, 3E033VG, 3E040VG, 3E043VG, 3E050VG, 3E053VG, 3E060VG, 3E063VG Administration, physiological systems and anatomical regions, introduction, hormone, insulin, codes for peripheral and central vein or artery and open or percutaneous approach
Type of Service  Medicine
Place of Service  Physician 


CIIIT, Diabetes
Chronic Intermittent Intravenous Insulin Therapy, Diabetes
Hepatic Activation, Diabetes
Metabolic Activation, Diabetes
Pulsatile Intravenous Insulin Therapy

Policy History

Date Action Reason
11/20/01 Add to Medicine section New policy
2/28/03 Replace policy Policy reviewed; no change in policy statement, additional references added
4/29/03 Replace policy Policy updated; policy statement unchanged
3/20/05 Replace policy Literature review updated for the period of 2003 through December 2004; policy statement unchanged
12/14/05 Replace policy Literature review updated for the period of 2004 through October 2005; policy statement unchanged. CPT coding updated
09/10/09 Replace policy The policy was returned to active review and updated with a literature search through June 2009. New references 8 and 9 were added to the policy. Policy statement is unchanged
9/16/10 Replace policy Policy review with literature search. New reference 6 added to the policy. Policy statement is unchanged
8/11/11 Replace policy Policy updated with literature search; policy statement unchanged. Reference 4 removed and references renumbered.
8/09/12 Replace policy Policy updated with literature search; reference 6 added; policy statement unchanged.
7/11/13 Replace policy Policy updated with literature search through June 7, 2013; reference 5 revised, and 9 and 10 added; policy statement unchanged.