Medical Policy


Subject:Hepatic Activation Therapy
Policy #:  MED.00065Current Effective Date:  04/15/2014
Status:ReviewedLast Review Date:  02/13/2014

Description/Scope

Hepatic activation, also referred to as chronic intermittent intravenous insulin infusion therapy (CIIIT), outpatient intravenous insulin therapy (OIVIT), pulsatile intravenous insulin therapy (PIVIT), pulse insulin therapy (PIT) or metabolic activation therapy (MAT), is a treatment of diabetes involving the delivery of insulin intravenously over a five to seven hour period, in a pulsatile fashion, using a pump controlled by a computerized program.  The dosages of insulin are adjusted, based on frequent blood glucose monitoring, and are designed to deliver a higher, more physiologic concentration of insulin to the liver than is delivered by traditional subcutaneous injections of insulin.

Position Statement

Investigational and Not Medically Necessary:

Hepatic activation therapy is considered investigational and not medically necessary as a treatment of diabetes.

Rationale

Individuals with type 1 diabetes require exogenous insulin therapy, with or without drug therapy with thiazolidinediones (to increase glucose uptake in the muscle, liver and gut) or metformin (to suppress hepatic glucose production).  A variety of different types of exogenous insulin are also available, i.e., short, medium, and long acting preparations.  Therefore, optimal management of type 1 diabetes requires an individualized regimen of dietary, drug, and insulin therapy, with the goal of a target HbA1c concentration of less than 7% to reduce microvascular and neuropathic complications of diabetes (American Diabetes Association, 2011).  Because of the many variables associated with diabetic management, randomized controlled clinical trials are necessary to validate treatment effectiveness; in fact, drug therapies for diabetic management are routinely studied in randomized controlled trials.

A search of the literature identified one randomized trial of CIIIT therapy.  Aoki and colleagues (1995) studied the effect of CIIIT on hypertensive medications in 26 subjects with type 1 diabetes and associated hypertension and nephropathy.  The 26 participants 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 participants were being treated with 4 daily insulin injections and had achieved acceptable HbA1c levels of 7.4%.  They also achieved acceptable baseline blood pressure control with a variety of medications.

While the study was randomized, it was not blinded in that sham CIIIT procedures were not performed.  Therefore, those receiving CIIIT received more intense follow up during this period.  During the treatment phase, participants reported a significant decrease in the dosage of antihypertensive medicines.  No difference in glycemic control was noted.  Since all subjects had adequate blood pressure control at baseline, the clinical significance of the decrease in antihypertensive dosage requirement associated with CIIIT is uncertain. 

Dailey and colleagues (2000) reported on the effect of CIIIT on the progression of diabetic nephropathy in a prospective, non-randomized trial of 49 individuals with type 1 diabetes.  A total of 26 participants were assigned to the control group, while 23 individuals were assigned to the treatment group who underwent weekly CIIIT.  Both groups reported a similar significant decrease in HbA1c levels 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 particularly since the decrease in HbA1c was similar in both groups.

In a pilot study (Weinrauch, 2007), ten individuals were treated with pulsatile intravenous insulin infusions and compared to a control group with eight individuals treated with subcutaneous insulin.  The investigators hypothesized renal function would be preserved via mechanisms "involving cardiac autonomic function, cardiac mass, or efficiency or by hemostatic mechanisms."  However, despite improvement of fuel oxidation noted by respiratory quotient, there was no significant difference between the control group and the treatment group in preservation of renal function.

In a randomized pilot study of pulsatile intravenous insulin (PIVIT), Weinrauch (2010) reported the results of 65 evaluable participants out of 90 enrollees with Type 1 diabetes and moderately severe (creatinine clearance greater than 30mL/min; mean 58.2 mL/min PIVIT cohort and 63.5 mL/min control) nephropathy.  All participants received standard therapy which included 3 to 4 insulin injections per day.  Those randomized to the treatment group received additional weekly intravenous pulsatile insulin with boluses of carbohydrates.  Primary endpoints included decreased progression of diabetic renal disease and deterioration of the eye.  During the follow-up period ranging from 6 to 22 months, the serum creatinine increased significantly from baseline in the control group (1.55 to 1.93; P=.0038), but not in the PIVIT treatment group (1.62 to 1.71; P = 0.1439).  Although creatinine clearance decreased for both cohorts, the differences were not significant in the group receiving weekly pulsatile insulin infusion.  Urine protein excretion did not significantly change at follow-up in either cohort.  There were no statistically significant differences in the grade and occurrence of progressive retinopathy between the two groups.  The authors concluded glycemia management was equally effective in both study groups and there was no beneficial retinal effect from PIVIT therapy.  Larger studies with longer follow-up are needed to further study the impact of PIVIT therapy on renal preservation in Type 1 diabetes.

All other studies of CIIIT therapy were case series.  Additionally, hepatic activation therapy is not discussed as a treatment option in the clinical practice recommendations of the American Diabetes Association (ADA).  In the 2013 ADA Standards of Medical Care in Diabetes, recommendations for diabetes treatment include multiple dose insulin injections (three to four injections per day of basal and prandial insulin) or continuous subcutaneous insulin therapy.

There have been several studies that suggest CIIIT may improve glycemic control, slow progression of nephropathy or facilitate blood pressure control.  However, the limited number of published studies lack adequate controls, randomization, and blinding, and the small sample sizes of the available studies preclude definitive conclusions regarding the health benefit of CIIIT.

In 2009, Centers for Medicare and Medicaid Services (CMS) issued a National Coverage Determination (NCD) noting that "OIVIT does not improve health outcomes."

Background/Overview

Hepatic activation, also referred to as chronic intermittent intravenous insulin infusion therapy (CIIIT), pulsatile intravenous insulin therapy (PIVIT), or metabolic activation therapy (MAT), is a proposed treatment of diabetes, involving the delivery of insulin intravenously over a five to seven hour period in a pulsatile fashion, using a pump controlled by a computerized program.  The dosages of insulin are adjusted, based on frequent blood glucose monitoring, and are designed to deliver a higher, more physiologic concentration of insulin to the liver than is delivered by traditional subcutaneous injections of insulin.  It is hoped that this therapy ultimately results in improved glucose control through improved hepatic activation.  Although the exact physiologic mechanism is unclear, Aoki, one of the principal investigators of MAT, proposes that, in diabetics, 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, five to seven-hour intravenous pulsatile infusions of insulin while the individual 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.

Definitions

Diabetes mellitus: a variable disorder of carbohydrate metabolism caused by a combination of hereditary and environmental factors and usually characterized by inadequate secretion or utilization of insulin, by excessive urine production, by excessive amounts of sugar in the blood and urine, and by thirst, hunger, and loss of weight.

Insulin: a protein hormone that is synthesized in the pancreas from proinsulin and secreted by the beta cells of the islets of Langerhans, that is essential for the metabolism of carbohydrates, lipids, and proteins, that regulates blood sugar levels by facilitating the uptake of glucose into tissues, by promoting its conversion into glycogen, fatty acids, and triglycerides, and by reducing the release of glucose from the liver, and that when produced in insufficient quantities results in diabetes mellitus.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

When Services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

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
  
ICD-9 Diagnosis[For dates of service prior to 10/01/2014]
 All diagnoses
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2014]
 All diagnoses
  
References

Peer Reviewed Publications:

  1. Aoki TT, Benbarka MM, Okimura MC, et al. Long-term intermittent intravenous insulin therapy and type 1 diabetes mellitus. Lancet. 1993; 342(8870):515-518.
  2. Aoki TT, Grecu EO, Arcangeli MA. Chronic intermittent intravenous insulin therapy corrects orthostatic hypotension of diabetes. Am J Med. 1995; 99(6):683-684.
  3. Aoki TT, Grecu EO, Arcangeli MA, et al. Chronic intermittent intravenous insulin therapy: a new frontier in diabetes therapy. Diabetes Technol Ther. 2001; 3(1):111-123.
  4. Aoki TT, Grecu EO, Prendergast JJ, et al. Effect of chronic intermittent intravenous insulin therapy on antihypertensive medication requirement in IDDM subjects with hypertension and nephropathy. Diabetes Care.1995; 18(9):1260-1265.
  5. Dailey GE, Boden GH, Creech RH, et al. Effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy. Metabolism. 2000; 49(11):1491-1495.
  6. Gill G, Williams G. Long term intermittent intravenous therapy and type 1 diabetes mellitus. Lancet.1993; 342(8878):1056-1058.
  7. Weinrauch LA, Burger AJ, Aepfelbacher F, et al. A pilot study to test the effect of pulsatile insulin infusion on cardiovascular mechanisms that might contribute to attenuation of renal compromise in type 1 diabetes mellitus patients with proteinuria. Metabolism. 2007; 56(11):1453-1457.
  8. Weinrauch L, 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):1429-1434.

Government Agency, Medical Society, and Other Authoritative Publications: 

  1. American Association of Clinical Endocrinologists Diabetes Mellitus Clinical Practice Guidelines Task Force. AACE Medical guidelines for clinical practice for the management of diabetes mellitus. Endocrine Practice. 2007; 13(Suppl 1):1-68.
  2. American Diabetes Association. Nutrition recommendations and interventions for diabetes: a position statement of the American Diabetes Association. Diabetes Care. 2007; 30(Suppl 1):S48-S65.
  3. American Diabetes Association. Standards of medical care in diabetes 2013. Diabetes Care. 2013; 36(Suppl 1):S11-S66.
  4. Centers for Medicare and Medicaid Services (CMS). National Coverage Determination: Outpatient intravenous insulin treatment (40.7). Effective December 23, 2009. Available at: http://www.cms.gov/mcd/index_list.asp?list_type=ncd. Accessed on December 9, 2013.
  5. National Collaborating Centre for Chronic Conditions. Type 1 diabetes in adults. National clinical guideline for diagnosis and management in primary and secondary care. London (UK): Royal College of Physicians; 2004. 171p.
Web Sites for Additional Information
  1. American Diabetes Association. Available at: http://www.diabetes.org/. Accessed on December 9, 2013.
Index

Chronic Intermittent Intravenous Insulin Therapy
CIIIT
Diabetes Mellitus, CIIIT in the Treatment of
Diabetes Mellitus, Hepatic Activation in the Treatment of
Hepatic Activation Therapy
MAT
Metabolic Activation Therapy
PIVIT
Pulsatile IV Insulin Therapy

Document History
StatusDateAction
Reviewed02/13/2014Medical Policy & Technology Assessment Committee (MPTAC) review. Updated References and Websites sections.
Reviewed02/14/2013MPTAC review. Updated References and Websites sections.
Reviewed02/16/2012MPTAC review. Updated References and Websites sections.
Reviewed02/17/2011MPTAC review. Updated References and Websites sections.
Reviewed08/19/2010MPTAC review. Updated Rationale, References and Websites sections.
 04/01/2010Updated Coding section with 04/01/2010 HCPCS changes.
Reviewed08/27/2009MPTAC review. Updated References and Websites sections.
Reviewed08/28/2008MPTAC review. References and websites updated. Updated Coding section with 10/01/2008 ICD-9 changes.
 02/21/2008The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.
Reviewed08/23/2007MPTAC review. References and Websites sections updated.
Reviewed09/14/2006MPTAC review. References section updated.
Revised09/22/2005MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.
Pre-Merger Organizations

Last Review Date

Document Number

Title

Anthem, Inc.

 

No prior document 
WellPoint Health Networks, Inc.

09/23/2004

2.01.06Hepatic Activation Therapy (CIIIT/PIVIT)