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.

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:

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.

 

A Pubmed literature search revealed no clinical trials reporting chronic intermittent intravenous insulin therapy.

 

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.

 

 

 

 

 

 

 

 

 

 

2018 Update  

 

A literature search was conducted through July 2019.  There was no new information identified that would prompt a change in the coverage statement.