Intermittent Intravenous Insulin Therapy
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This policy governs the coverage and clinical assessment of intermittent (pulsatile) intravenous insulin therapy, including variants such as hepatic activation therapy, metabolic activation therapy, pulsatile intravenous insulin therapy (PIVIT), and Trina Health artificial pancreas treatment; it affects members for whom these therapies are proposed and providers seeking reimbursement from Aetna.
No material clinical or coverage changes in this revision.
Coverage Determinations
Experimental and Investigational
Aetna considers the following procedures experimental and investigational because effectiveness has not been established:
These items are explicitly listed as experimental/investigational in the policy.
Coverage rationale (evidence-based)
Evidence summary and implications
Lasalvia-Prisco et al (2004) randomized trial (n=30) reported more frequent stable disease with insulin + methotrexate versus either agent alone but did not assess survival or long-term outcomes; findings require validation in larger, well-designed studies.
American Cancer Society commentary and subsequent reviews note no demonstrated long-term benefit and highlight risks of reduced chemotherapy dosing; small series (Damyanov 2012, n=16) reported preliminary signals (50% partial effect rate; median survival 11.7 months) but are insufficient to establish safety or efficacy.
This policy does not apply to the use of insulin infusions for the emergent management of diabetic ketoacidosis or hyperosmolar hyperglycemic state. Standard continuous insulin infusion protocols used for diabetic ketoacidosis or hyperosmolar coma are outside the scope of this bulletin and are not considered experimental or investigational under this policy.
Insulin potentiation therapy (IPT) should not be used as a substitute for standard, evidence-based chemotherapy regimens. The available literature is limited and does not demonstrate that lower-than-standard doses of chemotherapeutic agents administered with insulin achieve comparable antitumor effects. There are explicit concerns that reducing chemotherapy to fractions of the recommended doses when combined with insulin lacks evidence of safety and effectiveness and may be unsafe or ineffective.
The Centers for Medicare & Medicaid Services (2009) determined that outpatient intravenous insulin treatment (OIVIT) is not reasonable and necessary to treat diabetes or any other medical condition. CMS also concluded that diagnostic tests used in the context of OIVIT (for example, respiratory quotient, urine urea nitrogen, diagnostic blood glucose or potassium testing) do not produce results that can be reasonably used to manage patients with diabetes.
There are no published, peer-reviewed scientific studies that substantiate the safety and effectiveness of insulin potentiation therapy (IPT) across indications. Most reports are individual or small series; available small trials did not assess survival, quality of life, or long-term outcomes, and claims of benefit in the literature cannot be independently verified.
Codes and Billing
| A00.0-B99.9 | Certain infections and parasitic disease (range listed as not covered for indications in the CPB) |
| C00.0-D49.9 | Neoplasms (range listed as not covered for indications in the CPB) |
| M00.00-M25.9 | Arthropathies (range listed as not covered for indications in the CPB) |
Provider Requirements and Prior Authorization
Prior Authorization Required
Prior authorization is required per Aetna policy for outpatient intravenous insulin treatments (OIVIT/CIIIT) when considered for indications addressed by this policy. Providers should follow Aetna-specific prior authorization processes and submit supporting clinical information per payer instructions.
- Follow Aetna prior authorization process before scheduling OIVIT/CIIIT procedures.
- Submit clinical rationale, relevant history, and prior treatments with the PA request.
Procedures Identified as Experimental and Investigational
The policy explicitly identifies specific procedures as experimental and investigational because effectiveness has not been established. These include diagnostic testing performed in the context of intermittent intravenous insulin therapy (e.g., respiratory quotient, urine urea nitrogen, diagnostic blood glucose or potassium testing) and all forms of intermittent intravenous insulin therapy (also known as hepatic activation therapy, metabolic activation therapy, pulse/pulsatile intravenous insulin therapy, Trina Health artificial pancreas treatment, insulin potentiation therapy) for management of diabetes mellitus and other indications.
- Diagnostic tests of blood glucose or potassium, respiratory quotient, and urine urea nitrogen when performed in the context of intermittent intravenous insulin therapy are considered experimental/investigational.
- Insulin potentiation therapy (for cancer, arthritis, infectious diseases, and other conditions) is considered experimental/investigational.
- Intermittent intravenous insulin therapy (OIVIT/CIIIT/PIVIT/IPT) for diabetes or any other indication is considered experimental/investigational.
Evidence Insufficiency and Dosing Concerns
The evidence base is insufficient to support OIVIT/CIIIT/IPT. Published data are limited (small trials, short follow-up, and inconsistent outcomes) and do not demonstrate reasonable and necessary benefit. There are specific concerns about using chemotherapy at doses lower than those tested in clinical trials when combined with insulin—there is no evidence that reduced chemotherapy doses with insulin produce equivalent anti-tumor effects and this may risk undertreatment.
- Evidence is limited to very small studies and case reports; larger, well-designed trials with longer follow-up are lacking.
- Concerns exist about substituting lower-than-tested chemotherapy doses when used with insulin potentiation—this may compromise efficacy and safety.
No Specific Documentation Workflow Provided
There is no specific documentation workflow mandated in this policy for laboratory monitoring or test ordering when OIVIT/CIIIT is proposed. Providers should ensure that all clinical documentation, test results, and rationale for treatment decisions are captured in the medical record and submitted with any prior authorization request.
- No payer-prescribed documentation workflow for respiratory quotient, UUN, or other testing in OIVIT contexts is provided in this policy.
- Include laboratory results, test dates, and interpretation in the medical record and PA submission.
Documentation of Evidence and Outcomes
Providers should document and retain detailed evidence of investigational use and patient outcomes if considering or administering these therapies under clinical study or other circumstances. Capture trial data, dosing regimens (including exact insulin and chemotherapy doses), objective outcomes (tumor measurements per RECIST where applicable), adverse events, and duration of follow-up in the medical record.
- Record dosing details for insulin and any chemotherapy agents, administration dates, and monitoring results.
- Document objective outcome measures (e.g., tumor size changes, RECIST assessments), adverse events, and length of follow-up.
- Provide this documentation with any PA request or retrospective review to support medical necessity determinations.
Distinction from Standard Insulin Infusion Use (DKA/Hyperosmolar Coma)
This policy distinguishes OIVIT/CIIIT and related insulin potentiation approaches from standard insulin infusion use for acute metabolic emergencies. Use of insulin infusions for diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state is outside the scope of this policy and is not considered experimental/investigational.
- Do not apply the experimental/investigational determinations in this policy to insulin infusions used for DKA or hyperosmolar coma.
- When submitting prior authorization or clinical documentation, clearly state if insulin infusion is for standard acute metabolic management (DKA/HHS) versus investigational OIVIT/CIIIT.
Background and Scope
Chronic intermittent intravenous insulin therapy (also described as pulsatile intravenous insulin therapy, hepatic activation therapy, metabolic activation therapy, pulse insulin therapy, or Trina Health artificial pancreas treatment) delivers insulin as intermittent intravenous boluses or pulses, typically during multi‑hour outpatient sessions given in addition to usual subcutaneous insulin regimens. The proposed physiologic rationale aims to approximate physiologic portal insulin concentrations and to produce metabolic effects (for example, on glucose handling, renal function, blood pressure medications, or other parameters) by timed intravenous insulin dosing with monitoring of glucose and related measures. However, the effectiveness of this approach for diabetes management and other indications has not been established and is considered experimental and investigational.
Terms and Definitions
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