An Educational Service from GlycoMark Part 3 Interpretation and Clinical Use of 1,5-Anhydroglucitol Values An Educational Service from GlycoMark NOTE: Please see slide notes below each page for study and slide details GlycoMark is a registered trademark of GlycoMark, Inc. © GlycoMark, Inc. All rights reserved

GlycoMark 1,5-AG Value Correlation to Estimated Average Peak Glucose (eAPG) When A1C > 8%, 1,5-AG will almost always be <10 µg/mL due to 1,5-AG tissue depletion from constant hyperglycemic state When A1C < 8%, 1,5-AG reveals differences in postprandial glucose GlycoMark values correlate to the estimated average peak glucose after meals when the A1C is at 8% or lower. This chart shows the correlation. The goal is to keep 1,5-AG at 10 or higher. Levels below 6 indicate extreme hyperglycemic excursions. When A1C is over 8%, 1,5-AG levels will be depleted due to prolonged hyperglycemia. However, getting a baseline 1,5-AG test in this population can provide information for monitoring therapy changes. Dungan, K., Buse, J. et al. Diabetes Care, June 2006 Patent No. US 8,178,312 B2 May 15, 2012

Estimated Average Peak Glucose (eAPG) A1C 1,5-AG Paired Value Estimated Average Peak Glucose (eAPG) 8.3 % 8.1 7.9 7.8 7.7 7.5 2.7 µg/mL 5.1 4.4 3.5 6.5 19.6 258 mg/dL 211 219 235 199 171 7.4 15.1 3.4 175 237 7.2 19.2 5.7 205 7.0 18.1 2.0 172 294 6.8 6.7 20.8 5.8 170 204 6.4 16.8 6.3 2.3 173 200 276 10.2 9.2 4.3 184 187 221 23.2 4.9 169 213 Actual Clinical Data 1,5-AG identifies patients at higher risk so you can make needed therapy changes Similar A1Cs can have very different postmeal glucoses A1Cs <7.0% Meet ADA Guidelines This is actual clinical data that shows A1C by patient in rank order, then paired GlycoMark values and their corresponding estimated average peak glucose over the past 2 weeks. Note the differences in glycemic variability in the 2 patients at A1Cs of 7.4, 7.0 – and even at 6.4 and 5.7 – which are viewed as “excellent” glycemic control. Being able to identify these patients routinely and easily can help you to resolve problems with glycemic variability that can cause damage. At low A1Cs, low GlycoMark values can also indicate that there is potential hypoglycemia counterbalancing the hyperglycemia. This demonstrates how similar A1Cs, which are an average of blood glucoses over the past 60-90 days, can mask hyperglycemic postmeal spikes – and how some patients actually have relatively well-controlled postmeal blood sugars, so they may not need more expensive prandial medications to get them to goal. Low 1,5-AG values with low A1Cs may reveal undetected hypoglycemia Actual patient results from Diabetes Care Center, Hudson, FL and other paired lab results

Glycemic Blood Marker Comparison 1,5-Anhydroglucitol reflects recent glycemic variability not detected by A1C Measures therapy change effectiveness in 2-4 weeks Detects glycemic deterioration or improvement earlier 1,5-AG FBG or SMBG HbA1C Fructosamine or Glycated Albumin It is important to note that the GlycoMark test reflects recent glycemic variability in the last 2 weeks – often not reflected in the A1C, which is a 60-90 day measure of glycemic control. Therefore it can be useful in detecting deterioration in glycemic control earlier than an A1C and can measure therapy change effectiveness in as little as 2-4 weeks. 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Weeks Prior to Measurement

When patients have low 1,5-AG values, consider further assessment… Anything unusual in the past 2 weeks? Vacation/holiday – unusual food intake Stopped taking diabetes medication Steroid injection Illness or unusual stress Consider… Structured postmeal fingerstick glucose testing 24 hour glucose profile 3-day continuous glucose monitor Always ensure that nothing unusual has happened recently that could cause hyperglycemia prior to adjusting therapy. You may want to consider additional testing to address the appropriate problem – dietary or medications issues.

Limitations of 1,5-Anhydroglucitol Test Low values have been observed in Advanced kidney disease Stage 4 or 5; < 30 GFR; Dialysis Cirrhosis of the liver Reduced 1,5-AG liver biosynthesis Pregnancy Due to low and varying renal thresholds Drugs Acarbose Reduces absorption of carbs including 1,5-AG SGLT2 inhibitors Effect unknown (1,5-AG is transported via SGLT4) High values have been observed in Some IV hyperalimentation solutions Some Chinese medicines (Polygala, Tenuifolia, Senega Syrup) The most common conditions that can affect 1,5-AG values are Stage 4 or 5 renal failure with GFRs less than 30 Advanced cirrhosis of the liver Pregnancy due to changing renal thresholds You should also interpret results with caution in patients on acarbose and SGLT2 inhibitors. No common conditions or medications cause high values, so when you see high values, you can feel confident that patients’ postmeal spikes are controlled.

Suggested Personalized Therapy Algorithm Identify hidden PPH Monitor therapy changes So how do you apply GlycoMark to your practice? If you routinely order a GlycoMark test whenever the A1C is at 8% or less, you can identify patients who are having postmeal excursions. This can be done using a reflex test code, which gives you an A1C every time, but only a GlycoMark test if the A1C is at 8% or lower. If the GlycoMark value is greater than 10 µg/mL, consider targeting the fasting/baseline blood glucose. If the GlycoMark value is less than 10 µg/mL, consider targeting the postprandial glucose excursions with the drugs listed below. Dietary counseling may also be beneficial. You may also want to have the patient do pre- and postmeal blood sugars for a few days to identify a pattern – or put them on a continuous glucose monitor. Draw a GlycoMark test in 30 days and if the value is still < 10 µg/mL, consider another prandial medication adjustment. Continue doing this until the patient has a GlycoMark test result greater than 10 µg/mL. Modified from Dungan.Expert Rev Mol Diagn 8(1), 2008 Patent No. US 8,178,312 B2 May 15 2012

1,5-AG Assay Summary Clinically proven two week measure of glucose spikes1,2,3 Detects recent deterioration in glucose control missed by A1C Assesses therapy effectiveness after change4 Reinforces positive adherence to therapy and lifestyle changes4 Guides selection of the right medication to improve A1Cs while potentially reducing risk of hypoglycemia Fasting vs. prandial glucose Identify patients who need more frequent SBGM or CGM Appropriate selection of more costly prandial or injectable drugs In summary, GlycoMark is an accurate 2-week measure of postprandial glucose spikes, which can be used monthly to assess therapy changes and deterioration in control. It also can help you positively reinforce adherence to the patient’s therapy plan including diet and exercise. With similar A1Cs, the GlycoMark value can identify patients who need focused glucose testing, CGM, or more expensive prandial or injectable medications. It can also help prevent over-titration of baseline meds that could cause unnecessary hypoglycemia. 1 Wang, et al., Diabetes Metab Res Rev 2012; 28: 357–362. 2 Dungan, K., Buse, J. et al. Diabetes Care, June 2006 3 Yamanouchi, et al. Clin Sci (Lond) 2001 Sep;101(3):227-33. 4 McGill, et al, Diabetes Care, Vol 27, No. 8, August 2004

The Glycemic Triad Diabetes Panel 1,5-Anhydroglucitol Postprandial hyperglycemia marker (Last 14 days) Consider adding GlycoMark to your diabetic panel to identify and better manage those patients with postprandial glucose spikes that can lead to micro and macrovascular complications. Fasting Glucose HbA1C Baseline glucose marker (Current point in time) Average glucose marker (Last 60-90 days)

For more information For a listing of postprandial hyperglycemia outcome studies, please visit www.glycomark.com/postprandialhyperglycemia For a listing of studies about the 1,5-anhydroglucitol biomarker for postprandial hyperglycemia, please visit www.glycomark.com/product/studies For a 3-minute overview about the 1,5-anhydroglucitol biomarker, please visit www.glycomark.com/movie