Prediabetes and hemoglobin A1c levels in non-diabetics

• Hemoglobin A1C (HbA1C) levels above 5.4 percent in nondiabetics are associated with increased relative risk for developing coronary atherosclerotic heart disease (CAD), ischemic stroke (CVA) and mortality from any cause, as compared to those with HbA1C levels in the 5.0–5.4 percent range.
• Risk of developing diabetes mellitus over the ensuing fifteen years approximately doubles for each band of HbA1C from 5.0–5.4 percent, 5.5–5.9 percent and 6.0–6.4 percent.
• Underwriters observing HbA1C levels below 6.5 percent in nondiabetic individuals should not assume there is no associated increase of risk. As with any prudent underwriting assessment, it is essential to consider all risk factors presented before determining a final decision.

Today, prediabetes is a new word for a fast-rising problem around the world: an often undiagnosed metabolic condition which could lead to a more serious diagnosis of diabetes mellitus down the line. As many as 5.7 million Canadians can be considered to have prediabetes.¹ The trouble is, many do not know they have it, and prediabetes often has no symptoms at all. Yet if steps aren’t taken to control their blood sugar now, nearly 50 percent will go on to develop type 2 diabetes^.1

Prediabetes, also known as ‘impaired fasting glycemia’ (IFG) and ‘impaired glucose tolerance’ (IGT) is a metabolic condition with no symptoms. An additional prediabetes state also exists that arises transiently during pregnancy, otherwise known as gestational diabetes. 

Prediabetes is a growing global problem that is closely linked to obesity and is almost always a precursor to the development of type 2 diabetes. It is characterised by the presence of higher than normal blood glucose levels that are yet to reach diabetic levels. Physicians now understand that the health complications associated with type 2 diabetes often occur before a medical diagnosis is made.

In January 2011, the World Health Organisation (WHO) recommended that glycated Hemoglobin A1C (HbA1c), a test that gives an overall picture of what average blood sugar levels have been over a period of weeks, could be used as an alternative to standard glucose measures to help indicate the presence of diabetes mellitus. Since its introduction, not only has HbA1C testing has been found useful in determining the level of diabetic control but also, because of efficiency, has become an accepted method for confirming a diagnosis of diabetes mellitus. Today, HbA1C levels of 6.5 percent and greater are now considered to be diagnostic for this condition.

HbA1C levels below 6.5 percent have been found indicative of risk for future morbidity and mortality in those who are nondiabetic. HbA1C levels in nondiabetic participants in the Atherosclerosis Risk in Community Study (ARIC) indicated a future risk for developing not only diabetes, but also coronary atherosclerotic heart disease (CAD), ischemic stroke (CVA) and mortality from all causes.² After a follow up period of 15 years, HbA1C levels of <5.0 percent, 5.0–5.4 percent, 5.5–5.9 percent and 6.0–6.4 percent were found to represent respectively the following risks for developing diabetes: 6 percent, 12 percent, 21 percent and 44 percent.

HbA1C also appears to be an indicator of risk for development of macrovascular disease (both CAD and ischemic stroke) in nondiabetics.

Although minimal, relative risk for mortality from all causes begins to rise at HbA1C levels above 5.5 percent in a roughly linear fashion. Interestingly, those with HbA1C levels below 5 percent also appear to have a higher risk of mortality from all causes relative to those in the HbA1C 5.0 to 5.4 percent range. This results in a J-shaped mortality curve.

We know that HbA1C levels generally reflect a person's blood glucose levels over the previous eight to twelve weeks due to the attachment of hemoglobin to glucose. Therefore, since red blood cell survival time affects determination of HbA1C levels, alterations in the life of red blood cells may distort HbA1C values. Many common situations can result in falsely depressed HbA1C levels including: rapid red blood cell turnover due to hemolysis; production of many new red blood cells through anemia treatment with iron, vitamin B 12, folic acid or erythropoietin; recent blood transfusion; and splenomegaly.

With such processes associated with rapid red blood cell turnover, splenomegaly, or the necessity for blood transfusion may well be indicative of underlying conditions associated with increased mortality. However, the J-shaped mortality curve remains after significant hematologic problems are excluded, suggesting that further evaluation of health problems associated with the low-normal glycemic state need to be investigated.

A study of insurance applicants which evaluated mortality results associated with various levels of HbA1C obtained between 1993 and 2004 found that relative mortality was increased for HbA1C levels below 5.0 in the insurance applicant population as well.³
 Specific diseases associated with the increased mortality found in low HbA1C levels have not been well defined, but there appears to be an increase in cancer-related deaths.⁴  Interestingly, an association between low HbA1C values and hospitalization for liver disease has also been found.

Conversely, hematologic problems may also result in falsely elevated HbA1C levels. For example, when red blood cell production is depressed in some anemic states (e.g., untreated iron deficiency, vitamin B 12 deficiency or folate deficiency), a disproportionate number of older red blood cells may result in a false elevation of HbA1C levels. Values may also be falsely high in the presence of abnormal hemoglobin e.g. Fetal hemoglobin (HbF) or  isckle hemoglobin (HbS). Whereas chronic kidney disease may result in either falsely depressed or falsely elevated values.

Looking further ahead as an industry, evidence would suggest a closer study of the risks associated with elevated HbA1C levels in nondiabetics and how HbA1C might be used to help determine the risk of developing atherosclerosis.

With the increasing number of new cases of prediabetes on a global scale, and recognising the causal relationship between this condition and vascular disease, Munich Re’s view is that underwriters need to be aware more than ever of the implications this condition can have on mortality and morbidity. As with any prudent underwriting assessment, it is important to consider all risk factors presented before determining a final decision.

References
1. Canadian diabetes association
2. Selvin E, et al, Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults, NEJM 2010,362(9):800–11.
3. Stout R, et al, Relationship of Hemoglobin A1c to Mortality in Nonsmoking Insurance Applicants, Journal of Insurance Medicine 2007;39:174–81.
4. Aggarwal V, et al, Low Hemoglobin A1c in Nondiabetic Adults, Diabetes Care 2012,35:2055–2060.