Coverage Policy Manual
Policy #: 2012070
Category: Laboratory
Initiated: December 2012
Last Review: December 2023
  Biomarker Test, PreDx, Diabetes Risk Score

Description:
Individuals with diabetes have elevated blood glucose levels due to impaired insulin production and/or insulin resistance. Approximately 90% of affected individuals have type 2 diabetes. Type 2 diabetes is associated with other common conditions, including obesity and cardiovascular disease. Chronic hyperglycemia can result in complications such as chronic kidney disease, retinopathy, neuropathy, and poor circulation in extremities, resulting in amputation. The cost of care due to diabetes was estimated at $174 billion in 2007, with $116 billion as a result of direct medical costs.
 
The most widely used tests to diagnose diabetes and assess risk of developing diabetes are: glucose-based measurements, including fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and 2-hour plasma glucose during an oral glucose tolerance test (OGTT). Currently, there are a number of medications to treat type 2 diabetes.  The most commonly prescribed medicines include insulin, sulfonylureas, metformin, and thiazolidinediones.  Recently, Food and Drug Administration (FDA) has approved 2 new drugs (Symlin® and Byetta®; Amylin Pharmaceuticals Inc.) that have entered the market.  In addition to drug therapies to reduce type 2 diabetes, nonpharmacological lifestyle and dietary interventions resulting in weight loss have resulted in reduction in the incidence of type 2 diabetes. To prevent diabetes, predicting disease development during a prediabetes stage may reduce the health and economic burden of this condition. Therefore, in addition to glucose-based methods of risk prediction, many new diagnostic tests have been developed over the past decade. Genomics, proteomics, and metabolomics information is being used in risk models, and in many cases, multiple component tests are also being developed to improve diabetes risk prediction.
 
This policy addresses the PreDx® Diabetes Risk Score (DRS) test, a multiple-biomarker test to identify high-risk individuals who might develop diabetes within 5 years.
 
Tethys has developed a proprietary algorithm that combines seven biomarkers to quantify the risk of developing diabetes within 5 years. The model also includes age and sex. A diabetes risk score between 1 and 10 is calculated, with a higher score indicating an increased likelihood of developing diabetes within 5 years. Since the biomarkers are a combination of proteins and metabolites, they are measured using several different methods: ion-exchange high-performance liquid chromatography (HbA1c), chemiluminescent immunoassay (ferritin and interleukin 2 receptor alpha [IL2-Rα]), enzymatic (glucose), immuno-turbidimetric assay (Creactive protein [CRP]), and an enzyme-linked immunosorbent assay (adiponectin and insulin). The PreDx DRS is recommended for patients who do not have type 2 diabetes but are at increased risk for developing this condition. Patients to be considered include those with impaired fasting glucose, metabolic syndrome, or other risk factors, including family history, age > 45 years, presence of obesity, coronary artery disease, hypertension, low high-density lipoprotein cholesterol (HDL) (i.e., < 35 milligrams per deciliter), increased triglycerides, and belonging to an ethnic group with a higher prevalence of diabetes (for example, African American, Hispanic, Asian or Native American).
 
The PreDx test is no longer being offered by Tethys Bioscience.
 
 
 

Policy/
Coverage:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
PreDx Diabetes Risk Score testing for identifying high-risk individuals who might develop Type 2 diabetes does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, PreDx Diabetes Risk Score testing for identifying high-risk individuals who might develop Type 2 diabetes is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
Diabetes is a common chronic condition marked by elevated blood glucose levels due to impaired insulin production and/or insulin resistance. Tests for screening and diagnosis of diabetes are readily available. The test recommended for screening is the same as that for making diagnosis, with the result that a positive screen is equivalent to a diagnosis of pre-diabetes or diabetes (Cox, 2009).  Although about 25% of patients with type 2 diabetes already have microvascular complications at the time of diagnosis suggesting that they have had the disease for more than 5 years at the time of diagnosis (Harris,1992). It is still based on the American Diabetic Association (ADA) guidelines of 1997 or World Health Organization (WHO) National diabetic group criteria of 2006, which is for a single raised glucose reading with symptoms (polyuria, polydipsia, polyphagia and weight loss), otherwise raised values on two occasions, of either fasting plasma glucose (FPG) ³7.0 mmol/L (126 mg/dL) or with an oral glucose tolerance test (OGTT), two hours after the oral dose a plasma glucose ³11.1 mmol/L (200 mg/dL). (Cox, 2009).
 
The 1997 ADA recommendations for diagnosis of diabetes focus on the fasting plasma glucose, while WHO focuses on the OGTT (Cox, 2009). The glycated hemoglobin (HbA1c) and fructosamine is also still useful for determining blood sugar control over time. However, practicing physicians frequently employ other measures in addition to those recommended.  In July 2009, the International Expert Committee (IEC) recommended the additional diagnostic criteria of an HbA1c result ³6.5% for diabetes. This committee suggested that the use of the term pre-diabetes may be phased out but identified the range of HbA1c levels ³6.0% and <6.5% to identify those at high risk of developing diabetes.
 
 
As with the glucose-based tests, there is no definite threshold of HbA1c at which normality ends and diabetes begins (Cox, 2009). The IEC has elected to recommend a cut-off point for diabetes diagnosis that emphasizes specificity, commenting that this balanced the stigma and cost of mistakenly identifying individuals as diabetic against the minimal clinical consequences of delaying the diagnosis in a patient with an HbA1c level <6.5% (2009).
 
 
 
Olokoba and colleagues (2012) performed a review of current trends for Type 2 Diabetes based on a search of Medline, the Cochrane Database of Systemic Reviews, and citation lists of relevant publications.  The article discussed the history of the disease, as well as prevalence, current methods of diagnosis and treatment.  Diabetes caused 4.6 million deaths in 2011 (International Diabetes Federation) It is estimated that 439 million people would have type 2 diabetes by the year 2030 (Chamnan). The incidence of type 2 diabetes varies substantially from one geographical region to the other as a result of environmental and lifestyle risk factors (Zimmet, 2001).
 
Shafizadeh  and colleagues (2011) concluded in their study  on the comparison of the accuracy of the Diabetes Risk Score and Components of the Metabolic Syndrome in Assessing Risk (MetS) of Incident Type 2 Diabetes in Inter99 Cohort that  given the increasing rates of diabetes worldwide, better tools to identify subjects at highest risk of developing diabetes are needed. In this study the performance of the multi-marker DRS model was compared to presence of MetS factors for assessing risk of incident type 2 diabetes. DRS provided improved risk stratification in all MetS risk factor groups. Their opinion is that  DRS provides physicians with a tool to better identify subjects at increased risk for developing type 2 diabetes and allows for interventions to be targeted to those subjects at highest risk.
 
 
Sullivan and colleagues (2011) published a report on the cost-effectiveness of risk stratification for preventing type 2 diabetes using a multi-marker diabetes risk score.   The authors concluded that the cost-effectiveness of diabetes prevention can be improved by better identification of patients at highest risk for diabetes using the DRS.  The results based on the stratification of impaired fasting glucose ( IFG)-patients by the DRS method leads to improved identification and prevention among those at highest risk. At 5 years, the number needed to treat (NNT) in the IFG-only approach was 39 patients to prevent one case of diabetes compared to an NNT of 15 in the IFG + DRS approach. The study findings are limited by the generalizability of the DRS validation study and uncertainty regarding the long-term effectiveness of diabetes prevention.
 
Published data regarding the analytical validity of the PreDx DRS test are limited as noted by the Hayes GTE Report (November 2012).  Clinical validity studies have suggested that the PreDx DRS provides improved risk prediction for individuals at a high risk of developing diabetes within 5 years. In four retrospective studies, results showed that the PreDx DRS has results comparable to an OGTT.  The studies did show statistically significant better results when compared to the individual glucose-based measurements FPG and HbA1c.  In addition, the DRS showed improved performance when compared with two multiple-biomarker risk models, the San Antonio heart risk score, and the Framingham Diabetes Risk Score. However, even though the PreDx DRS better identified individuals who eventually developed type 2 diabetes in a 5-year period, only 25% to 30% of those classified as high-risk developed diabetes. Two of the independent studies used to validate the PreDx DRS results had missing biomarker data, which were then imputed using predefined assumptions. Furthermore, two of the four studies used data from the population in which the PreDx DRS test was developed. Therefore, there is a need to further validate this test in other independent populations. No studies evaluating the clinical utility of the PreDx DRS test were identified.  The Hayes Report included the cost of The PreDx DRS test at $300, according to a company representative from Tethys Bioscience Inc.  
 
Hayes GTE Report assigned a C rating for multiple-biomarker testing using PreDx DRS test to identify individuals at high risk of developing diabetes within 5 years (low analytical validity, moderate clinical validity, and very low clinical utility).
 
A search at www.clincialtrials.gov identified one on-going randomized trial for PreDx:   Assessing the Risk of Developing Type II Diabetes Using Serum Biomarkers in Patients Diagnosed With Obstructive Sleep Apnea (NCT01447251); estimated enrollment of 176 and estimated completion date of December 2012.
 
In Summary, additional studies are needed to validate the clinical utility and cost-effectiveness of the PreDx DRS test.  
 
2013 Update
A search of the MEDLINE database through November 2013 did not reveal any new published reports of controlled clinical trials assessing the clinical utility of the Pre-Dx® diabetes risk score. The coverage statement is unchanged.
 
2014 Update
A literature search conducted through November 2014 revealed that the PreDx Test is no longer being offered by Tethys Bioscience.
 
2017 Update
A literature search conducted using the MEDLINE database through October 2017 did not reveal any new information that would prompt a change in the coverage statement.   
 
2018 Update
A literature search was conducted through November 2018.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
81506Endocrinology (type 2 diabetes), biochemical assays of seven analytes (glucose, HbA1c, insulin, hs CRP, adiponectin, ferritin, interleukin 2 receptor alpha), utilizing serum or plasma, algorithm reporting a risk score

References: Chamnan P, Simmons RK, Forouhi NG, et al.(2011) Incidence of type 2 diabetes using proposed HbA1c diagnostic criteria in the EPIC-Norflok cohort: Implication for preventive strategies. Diabetes Care. 2011 Apr;34(4):950-6.

Cox EM, Elelman D.(2009) Test for screening and diagnosis of type 2 diabetes. Clin Diabetes 2009;4(27):132-138.

Harris MI, Klein R, Welborn TA, Knuiman MW.(1992) Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabetes Care 1992. Jul;15(7):815-819.

Hayes, Inc.(2012) PreDx® Diabetes Risk Score Hayes, Inc, November 8, 2102

Kolberg J, Wagenknecht L, Rowe MW, et al.(2012) Performance of a multi-marker diabetes risk score on the Insulin Resistance Atherosclerosis Study (IRAS), a multi-ethnic US cohort. Diabetes Metab Res Rev. 2012 Sep;28(6):519-26.

Nathan DM.(2009) International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1-8.

Olokoba AB, Obteru OA, Olokoba LB.(2012) Type 2 Diabetes Mellitus: A Review of Current Trends. Oman Med J. 2012 July; 27(4): 269–273.

Sacks DB, Arnold, M, Bakris, GL, et al.(2011) Position Statement Executive Summary: Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus. Diabetes Care, Volume 34, June 2011, 1419-23.

Shafizadeh TB, Moler EJ, Kolberg JA, et al.(2011) Comparison of Accuracy of Diabetes Risk Score and Components of the Metabolic Syndrome in Assessing Risk of Incident Type 2 Diabetes in Inter99 Cohort. PLoS One. 2011;6(7):e22863. Epub 2011 Jul 29.

Sullivan SD, Garrison LP Jr, Rinde H, et al.(2011) Cost-effectiveness of risk stratification for preventing type 2 diabetes using a multi-marker diabetes risk score. J Med Econ. 2011;14(5):609-16.

Urdea M, Kolberg J, Wilber J.(2009) Validation of a multimarker model for assessing risk of type 2 diabetes from a five-year prospective study of 6784 Danish people (Inter99). J Diabetes Sci Technol. 2009 Jul 1;3(4):748-55.


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.
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