1. Diabetes Prevention
Managing patients with High-Risk Pre-diabetes
The case for further evaluating patients classified as
pre-diabetes by A1C -- for indicators of glucose
tolerance and insulin resistance

2. Diabetes Prevention
Research has demonstrated that in patients classified as High-Risk
Prediabetes (Impaired Glucose Tolerance and Impaired Fasting Glucose)
intensive lifestyle and/or drug intervention can improve clinical and
economic outcomes
2

3. Intensive Lifestyle or Metformin Intervention Can
Reduce the Incidence of Diabetes in High-Risk
Adults
Key Points
 3234 individuals at Near-Term-High-Risk of incident diabetes (pre-diabetes) were randomized
to intensive lifestyle intervention, metformin, or placebo for 3-years
• Pre-diabetes was defined as
– Impaired Glucose Tolerance, elevated plasma glucose by OGTT (140 to 199 mg per dL),
AND
– Impaired Fasting Glucose, elevated plasma glucose by Fasting Plasma (100 to 124 mg dl) diabetes
• Lifestyle intervention reduced the incidence of diabetes by 58% compared to placebo and
Metformin by 31%
3
Diabetes Prevention Program Research Group. Reduction in the incidence of Type 2 Diabetes
with lifestyle intervention or Metformin. N Engl. J. Med. 2002
Take-Away Lifestyle changes and treatment with metformin both reduce the incidence of
diabetes in persons classified as High-Risk Prediabetes defined by Impaired Glucose
Tolerance (IGT) and Impaired Fasting Glucose (IFG)

4. Effectiveness and Cost-Effectiveness of Diabetes
Prevention among Adherent Participants
4
Herman et. al. American Journal of Managed Care. 2013
Key Points
 Over a 10-year period, among adherent participants, lifestyle intervention and
metformin were effective and cost-effective for diabetes prevention compared to
placebo
Undiscounted, Per Capita, Direct Costs of Medical Care, DPP/DPPOS – Adherence Analysis
Costs by Category Lifestyle Metformin Placebo
Outpatient visits 6741 3835 7325
Inpatient care 4748 4538 6856
ED visits 1855 1344 1825
Urgent care visits 1575 1836 1811
Calls to physicians 670 698 712
Prescription medications 6539 6972 6959
Self monitoring supplies and lab tests 1090 1994 1978
Total 23,218 24,217 27,468
Take-Away Interventions for diabetes prevention represent a good value for the money

5. Real-World Screening of Adults for
High-Risk Pre-Diabetes
The definitive test for Impaired Glucose Tolerance and High-Risk
Prediabetes – the Oral Glucose Tolerance Test – is not commonly used in a
primary care setting to screen for pre-diabetes / diabetes …
Adults with Insulin Resistance are 4 times more like to develop incident
diabetes
5

6. Diabetes Prevention
A1C Screening
 A1C tests have become common and the
increase in A1C testing over a 10 year period
accounts for the increase in prevalence of pre-
diabetes, from 11.6% to 19.3%
 The increased risk of incident diabetes ranges
from 9% to ~50% for A1C values in the range
of < 5% to 6.5%
 No clinical trials have been completed that
demonstrate the effectiveness of lifestyle or
drug prevention programs on diabetes
prevention in adults with prediabetes defined
by A1C test results
Real-Word screening for High-Risk Prediabetes
6
Take-Away A1C has become a standard of care in a primary care setting to screen for pre-diabetes
/ diabetes – however, prevention studies have focused on adults with High-Risk Pre-diabetes
classified by OGTT derived Impaired Glucose Tolerance, with FPG derived Impaired Fasting
Glucose
Categories of Increased Risk for Diabetes
(Prediabetes)
1. A1C of 5.7 to 6.4%* MOST COMMON
OR
2. Impaired Fasting Glucose (IFG)*
 Fasting plasma glucose (FPG) of 110 mg/dl to 125 mg/dl
OR
3. Impaired Glucose Tolerance (IGT)* LEAST COMMON
 75-gram OGTT for diabetes (prediabetes), 2-hour plasma
glucose of 140 mg/dl to 199 mg/dl
NOTE: OGTT and fasting glucose have been used to identify adults
as High-Risk Prediabetes and enrollment in lifestyle and/or drug
interventional studies

7. Implications of Risk Stratification for Diabetes
Prevention: The Case for HbA1C
Key Points
 HbA1c has been widely recommended for the diagnosis of diabetes
 Considerable ambiguity remains about how A1C should be used to
identify people with pre-diabetes or other high-risk states for
preventive interventions
 Although the top 15% of the nondiabetic A1C distribution is
estimated to account for ~50% of diabetes cases over 5 years ….
7
Gregg, et.al. Am J Prev Med. 2013
Take-Away No obvious threshold (A1C) exists to prioritize people for preventive
interventions

8. Low Positive Predictive Value of Hemoglobin A1C for
Diagnosis of Pre-diabetes in Clinical Practice
8
Gosmanov, et.al. The American Journal of Medical Sciences. 2014
Key Points
 Positive predictive value of HbA1C for diagnosis of pre-diabetes in clinical-practice
has not been well studied
 In a prospective study patients diagnosed with pre-diabetes based on A1C (5.7%
to 6.4%) underwent an OGTT as the gold standard to determine impaired glucose
tolerance (IGT)
 HbA1c in the 5.7% - 6.4% range not only identifies patients with OGTT-based
prediabetes, but also persons with Normal Glucose Tolerance (NGT) and Type 2
Diabetes
Take-Away The authors suggest that those with HbA1c of 5.7% - 6.4% should undergo an
OGTT to further classify and make a diagnosis (NGT, pre-diabetes [IGT], diabetes)

9. A Screening Protocol for Enrolling
Adults in Diabetes Prevention
Screening for High-Risk Prediabetes should be cost effective
9

10. A Screening Protocol for Individuals at High-Risk for
Diabetes and Interventions
Key-Points
Initial Screening
 Recommends that healthcare providers and/or health systems use (1) random plasma
glucose or (2) A1C, or (3) a glucose challenge test as opportunistic initial screening tests
 Initial screenings should prompt further evaluation of patients at high risk for diabetes
Follow up OGTT
 Identify high-risk patients by OGTT (impaired glucose tolerance IGT) for intensive lifestyle or
drug interventions
 Reduce false-positive A1C results
10
Chatterjee, et. al. Diabetes Care. 2013
Take-Away The identification of adults screened for pre-diabetes / diabetes using A1C testing
should include a confirmation test (OGTT) for Impaired Glucose Tolerance, however, the OGTT
in not commonly used in a primary care setting

11. A Screening Diabetes and Prediabetes Should be
Cost-Saving in Patients at High-Risk
Key-Points
• Screening for prediabetes using A1C and other tests was performed on 1,573 adults without
diabetes
• A definitive 75-gram OGTT was administered to adults screening positive for Pre-diabetes by A1C
• ~32% were positive for prediabetes by A1C and 13% confirmed positive for Impaired Glucose
Tolerance classified as High-Risk Pre-diabetes
• From a health economics perspective health system costs of screening and treatment of High-Risk
prediabetes are expected to be cost saving -- 10-20% lower than health system costs for no
screening and treatment
• The expected costs of screening and treatment of High-Risk prediabetes in a managed population
is expected to be $50 - $85 per/life for a 3-year intervention period – if screening is conducted on
adults with risk factors for diabetes (BMI, Age, BP, HDL) compared to $135 per/life if the entire
population is screened for prediabetes and treated
11
Chatterjee, et. al. Diabetes Care. 2013
Take-Away Screening for diabetes and High-Risk Prediabetes should target patients at higher
risk, particularly with risk factors (BMI, Age, BP, HDL), for whom screening can be most cost
saving

12. Quantose®
Key Points
Quantose® IGT
 A more convenient procedure for the clinician and patient to evaluate Impaired Glucose Tolerance
(IGT) status, compared to a 2-h OGTT procedure
 A single blood sample for Quantose® IGT can be collected at the point-of-care and does not require
patient follow through (compliance) with a subsequent visit to the clinic for the OGTT
 The clinician can make the decision to order Quantose® IGT during a follow-up encounter with the
patient while reviewing the outcome of an A1C test
Quantose® IR
 Also, with the same single blood sample, QuantoseIR provides information on patients with insulin
resistance – an early marker of diabetes risk and prior to positive results by A1C, fasting glucose, or
OGTT
 Individuals diagnosed with Insulin Resistance using Quantose® IR are 4 times more likely to develop
incident diabetes within 5 years
12
A simple and convenient alternative to the OGTT, and a test for Insulin
Resistance
Take-Away Quantose® IGT may be a valuable alternative to the OGTT to confirm High-Risk
Prediabetes in adults with A1C classifed prediabetes – those with Insulin Resistance by
Quantose® IR are 4 times more likely to develop incident diabetes within 5 years

13. Appendix
13

14. Quantose® IR for Insulin Resistance
 Quantose®IR identifies Insulin Resistance from a single fasting plasma specimen
 A panel of biomarkers are measured
 Insulin by automated chemistry
 AHB, LGPC, Oleate by ultra-high-performance liquid chromatography with mass spectrometric quantitation
 The Quantose®IR Score is generated using a proprietary algorithm based on the results from
insulin, AHB, LGPC, and Oleate tests
14
Technology Overview
Analyte Medical Rationale
Insulin
Alpha-hydroxybutyrate(AHB)
Gall WE et al. a-Hydroxybutyrate is an early biomarker of insulin resistance
and glucose intolerance in a nondiabetic population. PLoS One. 2010 May
28; 5(5):e10883.
L-linoleoylglycerophosphocholine
Ferrannini E et al. Early metabolic markers of the development of
dysglycemia and type 2 diabetes and their physiological significance.
Diabetes. 2013; 62(5):1730.
Oleic acid
Oh DY, et al., Gpr120 Is an Omega-3 Fatty Acid Receptor Mediating Potent
Anti-Inflammatory and Insulin-Sensitizing Effects. Cell, 2010. 142:687.

15. Quantose® IR – Sample Report
Insulin Resistance is an Early Indicator of Diabetes Risk
• An Early Stage Marker of
Diabetes Risk
Interpretation
 Patients with a Quantose®IR Score of 63
or higher are defined as Insulin Resistant.
This cutoff is defined by the top tertile of
IR scores from a gold-standard validation
study of 1277 hyperinsulinemic glycemic
clamp values of clinically healthy, non-
diabetic adults
15
Specimen Requirements
 Storage Temperature: Refrigerated 4C, or,
Frozen -20C to -80C
 Specimen Type: Plasma
 Collection Vial: EDTA (K2) / Lavender top
 Transport Vial: Thermo ScientifcTM NalgeneTM
Cryogenic Tube P/N 5000 0050
 Minimum Vial: 0.5 mL
 Shipping Conditions and Stability:
 Refrigerated 4OC Cold Pack / Overnight 96 hours or
 Frozen -20OC to 80OC Dry Ice / Overnight 5 months

16. Identify patients at High-Risk
for T2D
16
1
35% of
patients with
healthy A1C
values were
Insulin
Resistant, and
at increased
risk for T2D
70% of patients
with A1C of
5.7% - 6.4%
were Insulin
Resistant and
at a greater
risk for T2D
1 – Cobb et al. (2012) Quantose IR™: A prediabetes diagnostic that
correlates with multiple risk factors for metabolic and cardiovascular
diseases. Clin. Chem. 58; A61, abstract B-46
In a population of patients with “healthy” and “prediabetes” A1c values
Take-Away … those with IR by Quantose® IR were 4X more likely to develop
T2D within 5 years

17. Quantose® IGT for Impaired Glucose Tolerance
 Quantose®IGT identifies Impaired Glucose Tolerance from a single fasting plasma specimen
 A panel of biomarkers are measured
 Fasting glucose by automated chemistry
 Metabolites by ultra-high-performance liquid chromatography with mass spectrometric quantitation
 The Quantose®IGT Score is generated using a proprietary algorithm
17
Technology Overview
Analyte Medical Rationale
Glucose
Alpha-hydroxybutyrate(AHB)
Gall WE et al. a-Hydroxybutyrate is an early biomarker of insulin
resistance and glucose intolerance in a nondiabetic population.
PLoS One. 2010 May 28; 5(5):e10883.
L-linoleoylglycerophosphocholine
Ferrannini E et al. Early metabolic markers of the development of
dysglycemia and type 2 diabetes and their physiological
significance. Diabetes. 2013; 62(5):1730.
Oleic acid
Oh DY, et al., Gpr120 Is an Omega-3 Fatty Acid Receptor Mediating
Potent Anti-Inflammatory and Insulin-Sensitizing Effects. Cell, 2010.
142:687.
4-methyl-2-oxopentanoate (4MOP)
MeGlucose Using a Nontargeted Metabolomics Approach. Diabetes
2013; 62:4270.
Beta-hydroxybutyrate (BHBA)
Cobb, J et al, A Novel Test for IGT Utilizing Metabolite Markers of
Glucose Tolerance, J.Diabetes Sci.Tech. 2014; published online Sep.
26, 2014.
Serine Xie W et al, Genetic Variants Associated With Glycine Metabolism
Pantothenate (Vit B5)
Cobb, J et al, A Novel Test for IGT Utilizing Metabolite Markers of
Glucose Tolerance, J.Diabetes Sci.Tech. 2014; published online Sep.
26, 2014.

18. Quantose® IGT – Sample Report
Impaired Glucose Tolerance -- High Risk of Progression in patients with Pre-Diabetes
18
Interpretation
 Patients with a Quantose® IGT Score of 60
or higher are indicative of having impaired
glucose tolerance.
 This cut-off is defined by the top tertile of
scores from a gold-standard validation study
of 955 clinically healthy, non-diabetic people
recruited from 13 European countries having
a 12% prevalence of IGT (Cobb, 2015)
Specimen Requirements
 Storage Temperature: Refrigerated 4C, or,
Frozen -20C to -80C
 Specimen Type: Plasma
 Collection Vial: EDTA (K2) / Lavender top
 Transport Vial: Thermo ScientifcTM NalgeneTM
Cryogenic Tube P/N 5000 0050
 Minimum Vial: 0.5 mL
 Shipping Conditions and Stability:
 Refrigerated 4OC Cold Pack / Overnight 96 hours or
 Frozen -20OC to 80OC Dry Ice / Overnight 5 months