1) HbA1c is commonly used to assess long-term glycemic control but does not provide information about glucose variability and hypoglycemia risk. 2) Additional tests such as continuous glucose monitoring, glycated albumin, and 1,5-anhydroglucitol can help evaluate short-term control and glucose fluctuations not reflected in HbA1c. 3) Overreliance on HbA1c targets may overlook hypoglycemia risk, so a multifaceted approach considering other data is recommended for treatment decisions.

1. New information on the use of
HbA1c
as a compensation criterion
Valentyna Ocheretenko, Chair of the board UDF
Aleksandr Pkhakadze, MD, PhD
Maryna Neborachko, MD, MBA
Ukrainian Diabetes Federation
udf@ukr.net
a.g.pkhakadze@gmail.com
www.hba1c.ga

2. Which parameters we use to evaluate glucose’
metabolism?
• Fasting BG
• Postprandial BG
• Random BG
• HbA1c
• Glycated albumin
• 1,5-anhydroglucitol
• Glycemic profile
• Glucosuric profile
• Lipidogram
• The content of fibrinogen,
aggregation capacity assessment of
platelets

3. Glycated albumin (Fructosamine)
The indicator, which reflects the blood glucose level within 2-3
weeks.
The main indications for use: monitoring of diabetes status and
monitoring the effectiveness of its treatment within 2-3 weeks.

4. HbA1c
• Hemoglobin HbA1C (Glycated Hemoglobin) is a glycosylated subfraction of hemoglobin.
• It is a measure of both fasting and post-prandial glucose control over a 6-12 week period.
• It can be reported in percentage or mmol/mol. It estimates the average level of blood glucose.
• FDA has approved an HbA1C test for the diagnostic of diabetes. But there are contradictory opinions on this
matter.
• Glycated hemoglobin reflects the percentage of hemoglobin of the blood, irreversibly combined with
glucose molecules. HbA1c is formed as a result of the Mayar reaction between hemoglobin and blood
glucose.
• It was originally proposed by Koenig et al in 1976 for use in patients with diabetes mellitus.

5. Maillard reaction (reaction of the
sugar-amino condensation)
The chemical reaction between the amino acid and sugar, which, as a
general rule, occurs when heated.
An example of such a reaction is frying meat or baking bread, when a
typical smell, color and taste of cooked food occurs during the
heating of the food product.
These changes are caused by the formation of Maillard reaction
products.
Together with caramelization, the Mayar reaction is a form of non-
enzymatic darkening (stirring). Named after the French chemist and
physician Louis Camille Maillard, who was one of the first scientists
who investigated the reaction in the 1910s.

6. 1,5-Anhydroglucitol (1,5-G) or Glycomark
• Glycomark or 1,5 Anhydroglucitol, measures only post-prandial glucose
over a limited time period.
• The GlycoMark test is an FDA-cleared, non-fasting serum or plasma test
for monitoring blood glucose variability in people with diabetes.
• The GlycoMark test provides quantitative measurement of 1,5-
anhydroglucitol (1,5-AG) in serum or plasma. The test is for professional
use, and is indicated for the intermediate term monitoring of glycemic
control in people with diabetes.
Dungan J, Buse J et al. (1,5-Anhydroglucitol and Postprandial Hyperglycemia as Measured by Continuous
Glucose Monitoring System in Moderately Controlled Patients with Diabetes. Diabetes Care. 2006; 29:6:1214-
1219) http://glycomark.com

7. Which parameters we use to evaluate glucose’ metabolism?
• Mean (average) +- standard
deviation
• J index
• Coefficient of variance
• Glucose variability (time in range)
• Low blood glucose index (LBGI)
• High blood glucose index (HBGI)
• Average daily risk range
• Mean of daily differences
• Continuous overall net glycemic
action
• Mean amplitude of glycemic
excursions

8. Glycated albumin (GA) and 1,5-anhydroglucitol
(1,5-AG) can be used to assess glucose variability.
and prognosis of complications development.
GA is more useful for assessing short-term glycemic
control with type 2 diabetes.
The high ratio of GA / HbA1c reflects higher
fluctuations in glycemia regardless of the type of diabetes.
Determination of all 3 indicators - GA, 1.5-AG, HbA1c - allows
find people with higher rates of glycemic variability.

9. HbA1c
1) Seasonal variations
2) Ethnic differences
3) Genetically determined variations of hemoglobin
4) Difference by sex
5) Age changes

10. 33 factors that can affect the level of HbA1c
33 factors that are associated with lifestyle, hormone status, dietary habits and other lifestyle
factors that can affect the level of HbA1c
"Lifestyle factors that elevate HbA1c
1) Smoking
2) Opiates and Substance Abuse
3) Low air temperature
4) Air pollution
5) Psychological and social factors
6) Electromagnetic radiation
Medications that increase the level of HbA1c
7) Statins
There are only some factors, but it is obvious that not everything depends on the patient and
the doctor

11. Factors that can affect the level of HbA1c
• Cold weather can increase the level of HbA1c in people with type 2 diabetes.
• Patients with diabetes had a higher risk of having HbA1c> 7% in winter and spring
than in summer
• Low satisfaction with quality of life is associated with higher HbA1c.
• Long-term (1 year) and shorter (3 months) exposure to high concentrations of air
pollution is associated with an increase in HbA1c
• HbA1c was significantly increased after 3 months in patients receiving atorvastatin
• Moderate alcohol consumption can reduce HbA1c in both non-diabetics and people
with diabetes! Higher alcohol consumption was associated with a lower level of
HbA1c in adults in South Korea and in women in Japan.

12. 12
PROGENS HbA1c STUDY Nathan 2008
Average glycemia (90 day) = 41,0 + 16,2*HbA1c Average glycemia (90 day)=-46,7 + 28,7*HbA1c
R2=0,25 r=0,50 p<0,0001 R2=0.84 r=0,92 p<0,0001
HbA1c II visit
6 8 10 12
https://www.ncbi.nlm.nih.gov/pubmed/27695488

13. Maturation of CGM and Glycemic
Measurements Beyond HbA1c—A Turning Point
in Research and Clinical Decisions

14. International Consensus on Use of Continuous
Glucose Monitoring
• Glucose measurements are critical to
effective diabetes management.
• Although measurement of glycated
hemoglobin (HbA1c) has been the
traditional method for assessing
glycemic control, it does not reflect intra-
and interday glycemic excursions that may
lead to acute events (such as
hypoglycemia) or postprandial
hyperglycemia, which have been linked to
both microvascular and macrovascular
complications.

15. Recommendations
• HbA1c should be measured with a device that is
certified by the NGSP (National Glycohemoglobin
Standardization Program, www.ngsp.org) or the
IFCC (International Federation of Clinical Chemistry
and Laboratory Medicine, www.ifcchba1c.net).
• Clinicians and patients should target an HbA1c as
close to normal as possible without severe
hypoglycemia or a significant amount of non-
severe hypoglycemia while at the same time
individualizing glycemic targets according to
patient age, duration of diabetes, comorbidities,
and expected life expectancy, with “less-strict”
HbA1c targets for those more frail.
• CGM data should be used to assess hypoglycemia
and glucose variability.

16. Recommendations
• In adults with type 1 diabetes, severe hypoglycemia is more related to
duration of diabetes and socioeconomic status than HbA1c.
• In children aged 6–17 years old with type 1 diabetes or adults with type 2
diabetes (mostly receiving insulin or sulfonylureas), severe hypoglycemia
was most common among those with the lowest and highest
HbA1c levels.

17. A1C test considerations
• The HbA1C can give skewed results in people with certain genetic
traits that alter the molecules in their red blood cells.
• The ADA emphasizes that health care providers need to be aware
of these limitations, to use the correct type of HbA1C test, and to
consider alternate diagnostic tests (fasting plasma glucose test or
oral glucose tolerance test) if there is disagreement between
HbA1C and blood glucose levels.

18. Assessment of Glycemic Variability
• Numerous studies have focused on glycemic variability as an independent risk factor for
diabetes complications, particularly cardiovascular disease, and on the effects of glycemic
variability on cognitive function and quality of life.
• Acceptance of glycemic variability as a clinically valuable marker of glycemic control has
greatly expanded the understanding of glycemic control beyond HbA1c alone.
• The interpretation of average blood glucose is relatively straightforward, providing a
direct relationship to HbA1c. However, because glycemic variability is a reflection of a
dynamic process, understanding and measuring it is more complex.
• Glycemic variability is a process characterized by the amplitude, frequency, and duration
of the fluctuation.
• Both the amplitude and the timing of blood glucose fluctuations contribute to the risks
for hypoglycemia and hyperglycemia associated with diabetes.
• Increased glucose variability is consistently associated with mortality in the intensive care
unit and is a consistent predictor of hypoglycemia.
• Standard deviation (SD), coefficient of variation (CV), and mean amplitude of glucose
excursions are widely used to quantify glycemic variability.
• Stable glucose levels are defined as a CV <36%, and unstable glucose levels are defined
as CV ≥36%.

19. Appeal of ADA to the FDA
• Recently, epidemiological studies to assess the causes of death in type
1 diabetes (Edic, the Swedish registry of diabetes and the Scottish
registry of diabetes) have shown that hypoglycemia is responsible for
5% -10% of all deaths.
• In addition, a survey of more than 500,000 people with type 2 diabetes
showed an unacceptably high incidence of episodes of hypoglycemia:
• 45% noted moderate hypoglycemia
• 6% experienced severe hypoglycemia
• People with well-controlled diabetes - when achieving HbA1c level
below 7% - have a greater risk of hypoglycemia.

20. Level of HbA1c and diabetic food
• https://www.healio.com/endocrinology/news/in-the-journals/%7Ba807dad7-efa1-
484f-b109-9f7a8865fba5%7D/hba1c-wound-healing-unrelated-in-diabetic-foot-
ulcers
we did not see a clear association between HbA1c levels and wound
healing in patients who have developed foot ulcers
• https://www.umj.com.ua/article/124946/saharnyj-diabet-glikemicheskij-kontrol-i-
pravilnoe-ego-dostizhenie
• https://www.welldoc.com/insight/what-is-a1c/
• https://www.reuters.com/article/us-health-diabetes/doctors-slow-to-switch-
diabetes-treatment-when-drugs-dont-work-idUSKCN1IG364?feedT

21. False Low or False High
• http://journals.sagepub.com/doi/pdf/10.1177/1932296815572254
• Also is there anything besides anemia that can give a false result?
• Journal of Diabetes Science and Technology article:
'Quality of HbA1c Measurement in the Practice: The German
Perspective'
See Table 2 on page 6 of the pdf:
‘Reasons Why the HbA1c Measurement Gives a False Low or False
High’
http://journals.sagepub.com/doi/pdf/10.1177/1932296815572254

22. And more…
• To get the most accurate picture, I need all four indicators: fasting
blood glucose, HbA1c, post-meal glucose and fructosamine.
• But if I had to choose only one method of control, it would
definitely be post-meal glucose.https://chriskresser.com/why-
hemoglobin-a1c-is-not-a-reliable-marker/
• "Contrary to conventional wisdom, hypoglycemia occurs just as frequently
among those with poor glycemic control as it does in those achieving
near-normal glycemia," they concluded.
https://www.medpagetoday.com/endocrinology/diabetes/40764
• this article revisits the relationship between HbA1c and all-cause mortality
by a meta-analysis of observational studies.
https://www.ncbi.nlm.nih.gov/pubmed/25396402

23. Why we need additional tests beyond HbA1c?
Each episode of severe hypoglycemia can lead to death, but A1c does
not fix hypoglycemia.
• Treatment methods that reduce the risk of developing hypoglycemia
will save the patient, even if he does not measure HbA1c.
• In fact, reducing episodes of hypoglycemia may increase HbA1c, but
significantly reduce the risk of death, serious injury, or
hospitalization.
• The fear of hypoglycemia is the biggest barrier to tightening
glycemic control.

24. HbА1с good or bad
In a JDRF study using CGM, people with diabetes who
had HbA1c levels less than 7% experienced more than
90 minutes of hypoglycemia per day (below 70 mg /
dL).
Another recent study of the nightly level of
hypoglycemia in people with type 1 diabetes showed
even more worrying results:
• with a baseline HbA1c of 6.8%, patients had
hypoglycemia with a glucose level below 60 mg / dl
for two hours or more for 1 of every 1O night.
In 2009, hospitalizations due to hypoglycemia cost
the US more than $ 4.7 billions.

25. Many-faced 7% Ac - One measurement can not
fully describe the story

26. Many-faced 7% Ac - One measurement can not
fully describe the story

27. Glycemic Control and Excess Mortality in Type 1 Diabetes
In this study, patients with type 1 diabetes and a HbA1c level of
6.9% or lower had a risk of dying for any reason, including for
cardiovascular causes, twice as high as the risk in the control
group.
https://www.nejm.org/doi/full/10.1056/NEJMoa1408214

28. Regulatory decisions based not only on A1c, but also on the
results of other methods of diabetes control, would better take
into account the fundamental differences between long-term and
short-term risks, paying at least as much attention to the risk of
hypoglycemia as the HbA1c.
Why we need additional tests beyond HbA1c?

29. • One severe episode of low blood sugar can be fatal, but HbA1c
does not capture hypoglycemia.
Why we need additional tests beyond HbA1c?
www.hba1c.ga