Tailor your clothes and seek balance: Deep thinking on HbA1c control goals

*Only for medical professionals to read for reference.
What is HbA1c The most important hemoglobin (Hb) in adult red blood cells is HbA, which is composed of two α chains and two β chains.

HbA is divided into two types: HbA0 and HbA1.
The former is a non-glycated form and the latter is a glycated form [1].

HbA1 is further divided into three components: HbA1a, HbA1b and HbA1c.
Among them, HbA1c is the most important.
Its essence is the Amadori product formed by the non-enzymatic glycation of the N-terminal valine residue of the globin β chain with glucose, which accounts for about the total HbA1 Of 5/6[1].

 HbA1c reflects the average level of blood sugar within 3 months, and is currently the "gold standard" for evaluating the blood sugar control status of diabetic patients [2].

In clinical practice, how to apply HbA1c to help diabetes management? In January 2020, the "Expert Consensus on Glycated Hemoglobin Control Targets and Strategies for Adults with Type 2 Diabetes in China" was published [2]; in April 2021, the 2020 version of "Guidelines for the Prevention and Control of Type 2 Diabetes in China" was released [3], we Maybe you can find the answer from it.

 Why HbA1c became the "gold standard" In the late 1960s, HbA1c was discovered by people.

Subsequently, Samuel Lakhbar first described the phenomenon of elevated HbA1c in diabetic patients in a 1968 paper [4].

However, in the following time, HbA1c did not receive widespread attention, because most researchers at that time believed that the combination of glucose and hemoglobin must rely on the action of certain enzymes, so HbA1c could not independently reflect blood sugar levels; it was not until 1976 that HbA1c It is considered to be useful for clinical monitoring to reflect the blood sugar control status of diabetic patients [4].

 In 1993, the Diabetes Control and Complications Trial (DCCT) study found that the incidence of diabetes end-point events increased with the increase of HbA1c [5]; in 1998, the UK Prospective Diabetes Study (UKPDS) suggested that the newly diagnosed type 2 diabetes In (T2DM) patients, intensive control of HbA1c levels significantly reduces the risk of microvascular complications [6].

At the same time, for every 1% drop in HbA1c, the risk of stroke, myocardial infarction, and diabetes-related death are significantly reduced (Figure 1) [6].

The above studies have clarified the close relationship between HbA1c levels and diabetes complications.
As HbA1c increases, the relative risk of various complications increases significantly [7], thus establishing HbA1c as the "gold standard" for evaluating blood sugar control.

Figure 1 For every 1% reduction in HbA1c, the risk of cardiovascular events is significantly reduced.
Moreover, the Community Atherosclerosis Risk Study (ARIC) found that when 6.
0%≤HbA1c<6.
5%, the risk of diagnosing diabetes increased by 3.
48 times (HR 4.
48, 95%CI 3.
92-5.
13), when HbA1c≥6.
5%, the risk of diagnosing diabetes increased by 15.
47 times (HR 16.
47, 95%CI 14.
22-19.
08), which also provides evidence for exploring the HbA1c cut point for diagnosing diabetes stand by.

 Based on clinical evidence, the 2010 American Diabetes Association (ADA) guidelines included HbA1c≥6.
5% in the diagnostic criteria for diabetes for the first time [9].

The guidelines recommend that the diagnostic test should be measured using a method certified by the National Glycohemoglobin Standardization Program (NGSP), and standardized by the results of the DCCT study [9].

Subsequently, in 2011, the WHO also affirmed the value of HbA1c for the diagnosis of diabetes [10].

 The 2020 edition of the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China" included HbA1c in the diagnostic criteria for diabetes for the first time (Figure 2), and pointed out that in order to be in line with the WHO diagnostic criteria, it is recommended to adopt standardized testing methods and have strict quality control (US National Glycated Hemoglobin Standardization Program) , Medical institutions under the China Glycated Hemoglobin Consistency Research Program can use HbA1c≥6.
5% as a supplementary diagnostic criterion for diabetes [3].

Figure 2 The 2020 edition of the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China" Diabetes Diagnostic Standard HbA1c Control Target Controversy Multiple large-scale clinical studies have confirmed that intensive blood glucose control can improve patient prognosis, mainly reflected in the decreased risk of microvascular complications, but for large blood vessels The benefits of complications are still controversial.
Strict HbA1c control does not bring consistent macrovascular benefits (Figure 3), and even increases the risk of death [5, 6, 11-18].

The different interpretations of many studies have led to differences in the HbA1c goals set by different academic organizations.

Figure 3 Enhanced HbA1c control brings microvascular benefits, but does not bring consistent macrovascular benefits.
In 2018, the American College of Physicians (ACP) set the HbA1c target value for most adult T2DM patients at 7% to 8%[2 ].

The "Expert Consensus on HbA1c Control Targets and Strategies for Adults with Type 2 Diabetes in China" believes that while hypoglycemic therapy avoids risks, the benefits of hypoglycemic therapy should not be ignored [2].

With the advent of some hypoglycemic drugs, clinicians have the ability to enable many patients to reduce HbA1c to less than 7.
0% without increasing the risk of hypoglycemia and weight (ie "safety compliance").

In this context, it is unreasonable to set the HbA1c target value for most adult patients with T2DM at 7%-8%.

Different from the ACP guidelines, the Chinese Medical Association Diabetes Branch (CDS), ADA, International Diabetes Federation (IDF) and Canadian Diabetes Association guidelines all recommend HbA1c control target <7.
0% [2].

Insulin is a powerful tool for glucose control.
Many studies have confirmed that the twice-daily injection of insulin aspart 30 can effectively reduce HbA1c, improve blood sugar control and reduce the occurrence of hypoglycemic events [19-26] (Figure 4, 5). Figure 4 Insulin aspart 30 twice daily injection regimen can effectively reduce HbA1c Figure 5 Insulin aspart 30 twice daily injection regimen has fewer hypoglycemic events.
HbA1c control goal: maintain the balance of benefit and risk HbA1c control goal is tailored The art of, should follow the principle of individualization, that is, implement hierarchical management according to the patient’s age, course of disease, health status, risk of adverse drug reactions and other factors, and implement the risk/benefit ratio, cost/benefit ratio, and accessibility of blood sugar control Make scientific evaluations in order to achieve a reasonable balance [3].

 The 2020 edition of the “Guidelines for the Prevention and Treatment of Type 2 Diabetes in China” lists the main influencing factors for the setting of individualized glucose-lowering goals for adult T2DM.
The influencing factors are divided into invariable factors (age, course of disease, diagnostic life span, comorbidities, complications, The tolerance of side effects such as hypoglycemia) and variable factors (patient's subjective willingness, resources and support system, whether to use drugs that increase the risk of hypoglycemia) are two major categories, a total of nine subcategories [3] (Figure 6).

 Figure 6 The main influencing factors of individualized HbA1c control goals for adult patients with type 2 diabetes mellitus Most non-pregnant adults with T2DM have HbA1c control goals of <7.
0%, younger age, shorter course of disease, longer life expectancy, and no complications , T2DM patients without cardiovascular disease can adopt more stringent HbA1c control goals (such as <6.
5%, even as close to normal as possible) without hypoglycemia or other adverse reactions.

Patients who are older, have a longer course of disease, have a history of severe hypoglycemia, have a short life expectancy, have significant microvascular or macrovascular complications or severe comorbidities can adopt a relatively loose HbA1c target [2, 3].

 Figure 7 HbA1c control goals in patients with T2DM and CKD.
Summary HbA1c is the "gold standard" for evaluating blood glucose control in diabetic patients.

The 2020 edition of the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China" included HbA1c in the diagnostic criteria for diabetes, reaffirming the importance of HbA1c in blood glucose management.

HbA1c levels are significantly related to microvascular and macrovascular outcomes.
Controlling HbA1c standards is the top priority of comprehensive diabetes management.
However, HbA1c control goals should be tailored to suit the individual and follow the principle of individualization to achieve a balance between benefits and risks.  References: [1]Su Qing.
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[22]Yang W, et al.
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[25] Yang Wenying, et al.
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Diabetes Care, 2005, 28(2):260-5.
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Exp Clin Endocrinol Diabetes, 2006, 114(9):527-32.
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Diabetes Obes Metab, 2009, 11(1):27-32.
[22]Yang W, et al.
iabetes Care, 2008, 31(5):852-6.
[23]Gao Yan, Guo Xiaohui.
Chinese Journal of Endocrinology and Metabolism, 2008 , 24(6):616-619.
[24]Yang W, et al.
Current Medical Research &Opinion, 2010, 26(1):101-107.
[25] Yang Wenying, et al.
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[26] Ji Linong, et al.
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iabetes Care, 2008, 31(5):852-6.
[23] Gao Yan, Guo Xiaohui.
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[24]Yang W, et al.
Current Medical Research &Opinion, 2010, 26(1):101-107.
[25] Yang Wenying, et al.
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[26] Ji Linong, et al.
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[23] Gao Yan, Guo Xiaohui.
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[24]Yang W, et al.
Current Medical Research &Opinion, 2010, 26(1):101-107.
[25] Yang Wenying, et al.
Chinese Journal of Diabetes, 2012, 4(10):607-12.
[26] Ji Linong, et al.
Chinese Journal of Diabetes, 2011,19( 10):746-751.