Use of the Estimated Average Glucose (eAG) in Patient Care Part 1 of 2

A Typical Patient Encounter “So, Mrs. Smith, it looks like you do have diabetes. Your repeat fasting blood sugar was 178, and as you recall the first one was 187. Over 126 is diabetes. Also, your hemoglobin A1c was way too high at 8.6%. Normal is less than 6%. We need to get it below 7%.” Let’s start with a scenario that many of us have experienced before with a newly diagnosed patient. (Read health care provider speech.)

A Typical Patient Encounter “What’s a hemoglobin A…whatever you said? I remember my hemoglobin was low when I was pregnant. What were those other numbers? What do you mean, 7%...of what?” (Read patient speech).

 __% = G G G G G G G G G G G G G G G (This slide is animated as if you are drawing out the explanation. Click enter or down arrow as you talk.) [Enter, Enter] Your body is full of blood vessels. [Enter] Inside the blood vessels are red blood cells. [Enter] The red blood cells carry a protein called hemoglobin that carries oxygen. [Enter] Your red blood cells swim in your bloodstream [Enter] for about 3 or 4 months before they die. [Enter] Normally we have a certain amount of a sugar called glucose in our blood. [Enter] Some of that glucose gets stuck on the hemoglobin. [Enter] When you have diabetes, you have too much glucose in your blood, [Enter] and even more gets stuck on the hemoglobin. [Enter] The way we measure your hemoglobin A1c is to draw your blood [Enter] and send it to the lab. [Enter] They measure how much hemoglobin has glucose stuck on it [Enter] and divide it by [Enter] the total amount of hemoglobin [Enter], and that equals [Enter] a percentage that’s your hemoglobin A1c. G G  = __% G G G G

Uh… ??? Uh… Now does this seem like a patient who’s ready to work on her diabetes control?

It’s Not Just Confusing for Newly Diagnosed Patients High levels of testing of HbA1c for patients with known diabetes (> 90%). Of patients with test in past 6 months: 66% did not know result 25% accurately reported within 1% range (< 7%, 7-8%, 8-9%) 9% inaccurately reported within 1% range The previous example was a newly diagnosed patient, but the confusion about A1C happens to many patients with established diabetes, as well. It’s known that A1C measurements are regularly done in the majority of patients with known diabetes. However, this study took a group of patients whose A1C had been measured during routine care within the prior 6 months, and asked them if they knew the results. 66% couldn’t give any number whatsoever. 25% were able to state their A1C results within a 1% range (for example, if a patient’s A1C had been 7.5%, the researchers counted a correct answer as anything between 7.0% and 7.9%). The remaining 9% stated a number, but it wasn’t correct within that 1% range. Heisler, Diabetes Care 28:816,2005

The Clinical Dilemma HbA1c: useful for research, risk prediction, target of therapy Well standardized HOWEVER, difficult to explain to patients Concept of % is not intuitive Glucose more familiar to patients from self-monitoring or from laboratory glucose results So we face a clinical dilemma. Clearly, the A1C has been extremely useful in research, as a predictor of risk (such as microvascular complications), and as a target of therapy. The assay is now well standardized. However, as many of us know, it’s difficult to explain to patients. The concept of a low number expressed as a percent is not intuitive. Most patients are much more familiar with glucose numbers and units, either from their home glucose monitoring or even from laboratory glucose results.

The Concept of Average Glucose We tell patients the HbA1c reflects their “average glucose over 2-3 months” But: do we know this for sure? So what about this concept of “average glucose”. We certainly tell patients that the A1C reflects their “average glucose over 2-3 months”, but do we know this for sure?

Number of glucose tests per patient Study Year Cohort Study period (weeks) Number of glucose tests per patient per 1-3 months Svendsen 1982 15 T1DM 5 200-300 Nathan 1984 21 T1DM 8 DCCT 2002 1439 T1DM 12 7 Hempe 128 T1DM 4 80 Murata 2004 2007 182 T2DM 22 T1DM 3 Normals 180 24,000 (CGMS) Well, you might say, “Of course we do.” But it turns out that the previous studies that “established” this were somewhat sparse on data. Most included only patients with type 1 diabetes, who as you know tend to have very erratic blood glucose levels. Most were based on small numbers of patients, as you can see. The DCCT data [ENTER to get oval highlight] are what were used to develop the tables that we have all seen. This is the table of A1C converted to mean glucose that’s in the ADA Standards of Care document each year. Although this table was based on 1439 DCCT participants’ data, the correlation of A1C with average glucose is based on a SINGLE DAY’S 7-point meter glucose readings per A1C measurement.

The A1C-Derived Average Glucose (ADAG) Study International study designed to: Carefully look at relationship between HbA1c and average glucose Determine the mathematical relationship between the two for reliable conversion Establish that the relationship is valid across: - Diabetes types - A wide range of HbA1c levels and age - Different races/ethnicities In part because of the sparse data on the relationship of A1C to average glucose, the A1C-derived average glucose, or ADAG study was launched several years ago. This was an international study designed to carefully look at the relationship between A1C and average glucose, determine the exact mathematical relationship between the two for reliable conversions, and also to establish that the relationship is valid across different types of diabetes (including non-diabetic individuals), a wide range of A1Cs, different ages, and different races and ethnic groups. The results of the ADAG study were published in Diabetes Care in August 2008. Nathan et al, Diabetes Care 31:1473, 2008

ADAG Study Centers Cameroon United States Denmark Italy The Netherlands United States Boston New York San Antonio Seattle India (site dropped due to specimen handling issues) The study sites are listed here, and included sites in Africa, Europe, and the US. There also was a site in India, but unfortunately the data from this site couldn’t be used due to specimen handling issues related to refrigeration.

Participants in ADAG Goal was to recruit people with With a range of Type 1 diabetes Type 2 diabetes No diabetes With a range of Ethnicity/race HbA1c levels Excluded those with conditions that would interfere with measurement/interpretation of HbA1c or glucose The goals was to recruit people with Type 1 diabetes, Type 2 diabetes, and No diabetes With a range of Ethnicities/races, and a range of HbA1c levels Because this was a study looking at the correlation of two measurements under normal conditions, the study xcluded those with conditions that would interfere with measurement or interpretation of HbA1c or glucose (such as hemoblobinopathy, increased or decreased red cell turnover due to anemia or kidney disease, etc.).

Measures of Glycemia in ADAG Study CGM (calibrated by 8-point glucose profiles with Hemocue meter) for at least 48 hours at baseline and every month for 3 months 7-point glucose profiles for 3 days per week with One Touch Ultra meter HbA1c at baseline and monthly X 3 months with DCCT-aligned assay in a central laboratory Four measures of HbA1c to assure stable control, but only final value used for correlation with prior 3 months’ glucose readings The study did a number of measurements of glycemia over 3 months: Continuous glucose monitoring for at least two days per month. The CGM device was calibrated with 8 measurements per day with a highly reliable glucose meter. 7-point glucose profiles (pre- and post-prandial and bedtime) for at least 3 days per week for 3 months And a standardized A1C monthly. The monthly measures were used to assure that participants had stable glucose control. However, only the 3 month value was used for correlation with all the glucose readings for the past 3 months.

ADAG Study Flow Total Enrolled 661 Eliminated from analysis 154 (23%) - Dropped out or excluded 91 (14%) during study - Inadequate CGM 11 (2%) - Inadequate HbA1c samples 52 (8%) Listed here is the participant flow in the study. You can see that 661 people were enrolled. Of that, 154 could not be used in the final analysis, either due to dropping out of the study or due to specimen problems.

Baseline Characteristics of ADAG Participants Type 1 Type 2 Non-DM Total Number 268 159 80 507 Age 43 + 13 56 + 9 40 + 14 46 + 14 Gender (% F) 52% 50% 69% 54% Race/Ethnicity White 93% 73% 71% 83% African/Af-Am 2% (5) 13% (21) 15% (12) 8% (38) Hispanic 6% (15) 8% (12) 8% (39) Treatment Pump / ≥3 inject/day 47% / 53% Diet only/ 10% Oral agent only Insulin only 19% Insulin & oral You can see here the baseline characteristics of the ADAG participants. There are significant numbers of type 2 participants and non-diabetic participants, although a larger number had type 1. There are small groups of Hispanic and African or African-American participants, although 83% were Caucasian. Of the type 1 subjects, all were on either pumps or multiple daily injections. The type 2 subjects used a variety of therapies ranging from no medications to insulin.

ADAG Study: Distribution of Baseline HbA1c 44% Number of subjects 38% Normal D i a b e t c 18% The baseline A1Cs were fairly widely distributed. Baseline HbA1c (%)