The Prediabetes Puzzle: What the Blood Tests Mean

The Prediabetes Puzzle: What the Blood Tests Mean

by Gary M. Pepper, M.D. with Samuel Jeans, MSc

As an endocrinologist, I frequently encounter patients who are confused about whether they have diabetes or prediabetes. Many have been told that their blood sugar levels were above normal on recent blood tests, possibly indicating prediabetes. However, this concern is often unfounded. So why is this scenario so common?

I believe that commercial lab facilities are partially responsible. Their routine procedure is to flag blood sugar levels over 99 mg% as abnormally high, which can result in many false positive diagnoses of abnormal glucose metabolism. But why do medical facilities continue to follow this protocol?

To understand this, let’s take a closer look at how prediabetes and diabetes are diagnosed.

Diabetes type 2 is a metabolic disease in which the body’s insulin production and sensitivity is impaired, resulting in consistently higher-than-normal blood glucose levels.

At current estimates, between 1 in 10 and 1 in 11 of the world’s population have diabetes.

Around 90% of those who have diabetes have type 2 diabetes.  This is a disease in which the body is able to create insulin but either can’t create enough insulin or has become resistant to it. Insulin helps move glucose (sugar) from the blood into the cells that need it for energy. Diabetes complications include nephropathy (kidney), retinopathy (eye), and vascular disease. In the worst cases, this can lead to complete loss of feeling in the feet, kidney failure or blindness.

The complications of diabetes grow worse with age. At age 50, those with diabetes live six years less on average than those without, according to the CDC. However, early intervention and proper treatment have been shown to restore life expectancy to close to normal levels – especially if prediabetes is identified early.

It’s certainly possible to prevent, delay or change the course of diabetes. However, this depends on a robust and accurate assessment of prediabetes and the timely prescription of medication and lifestyle interventions.

Defining Prediabetes

People don’t become diabetic overnight. Before diabetes is established, individuals go through a stage of prediabetes that can last anywhere between 2 to 5 years. The effects of prediabetes are largely asymptomatic or invisible, and it’s often flagged on coincidental or routine blood tests.

The CDC estimates that 96 million adults in the US – over a third of the population – likely have prediabetes. Similar levels are observed across other developed countries.

In the USA, incidence rates of diabetes have doubled in the last 20 years, and diabetes is the 7th leading cause of death, and this is likely underreported.

Harvard Health cites that many people totally miss prediabetes or don’t take sufficient action to prevent it from developing into full-blown diabetes. As few as 10% of people with prediabetes are aware that they have it. Around 5 to 10% of cases of prediabetes convert into diabetes annually.

On the positive side, lifestyle changes can prevent as many as 70% of cases of prediabetes from turning into diabetes. As such, accurate and timely diagnosis and intervention are a top priority. But as ever, it isn’t as straightforward as some perceive.

Testing and Diagnosing Prediabetes and Diabetes

Testing blood glucose levels and response is critical for diagnosing prediabetes, as prediabetes is usually asymptomatic and neurologic and vascular pathology are absent.

Recommendations for who and when to screen for diabetes and prediabetes have been provided by several authoritative organizations and are summarized by metabolism.com in an earlier article.

However, capturing blood glucose levels and robustly diagnosing prediabetes is challenging, and leading health authorities provide varying and non-consistent advice.

There are four main ways to test and measure blood glucose to diagnose prediabetes and diabetes. Here’s an overview of each:

1: HbA1C Test

The HbA1C test (glycosylated hemoglobin A1c) measures average blood sugar level over a long period, typically the past 2 or 3 months. It achieves this by measuring the amount of hemoglobin in the red blood cells coated with glucose (HbA1c).

An HbA1C below 5.7% is considered normal, between 5.7 and 6.4% indicates prediabetes, and 6.5% or higher indicates diabetes.

2: Fasting Blood Sugar Test

A fasting blood sugar test measures impaired fasting glucose (IGT). The blood test is taken after an overnight fast (not eating).

The American Diabetes Association defines a fasting blood sugar level of 99 mg/dL or lower to be normal, 100 to 125 mg/dL indicates prediabetes, and 126 mg/dL or higher indicates diabetes.

3: Glucose Tolerance Test

Glucose tolerance tests measure impaired glucose tolerance (IGT). This blood test measures your blood sugar before and after drinking a solution containing glucose. The WHO advises that the test is taken 2 hours after ingestion of 75 g of oral glucose.

Additional measurements may be taken at 1 and 3 hours or at 30 to 60-minute intervals. Similarly to a fasting blood test, individuals must fast overnight before the test.

At 2 hours, a blood sugar level of 140 mg/dL or lower is considered normal, 140 to 199 mg/dL indicates prediabetes, and 200 mg/dL or higher indicates diabetes.

4: Random Blood Sugar Test

In some cases, clinicians may choose to take blood sugar randomly, known as a random blood sugar test. This is taken at any point, with no fasting.

It’s not robust but indicates diabetes with a blood sugar level of 200 mg/dL or higher. This often initiates other blood investigatory tests for diabetes.

Diagnostic Criteria for Diabetes vs Prediabetes

Hb A1c  Fasting glucose    OGTT (2 hours)
Diabetes 6.5% or higher 126 mg% or higher 200 mg% or higher
Prediabetes 5.7% to 6.4% 100 to 125 mg% 140 to 199 mg%
Normal 5.7% or less 99mg% or less 140 mg% or less

Debates Surrounding Diabetes Diagnostics

Measuring glucose levels is one thing, but relating findings to prediabetes on a patient-by-patient basis is another.

First off, there are four tests to choose from, and global health authorities don’t advise the same test, let alone the same test result criteria.

● The World Health Organization (WHO) defines prediabetes with two parameters. First, they use impaired fasting glucose (IFG), defined as 6.1-6.9 mmol/L (110 to 125 mg/dL). Secondly, they use impaired glucose tolerance (IGT), defined as 2 h plasma glucose of 7.8-11.0 mmol/L (140-200 mg/dL).

● The American Diabetes Association (ADA) uses the same cut-off for IGT but a lower cut-off for IFG (100-125 mg/dL). The hemoglobin A1c test is common in the US, with 5.7% to 6.4% indicating prediabetes.

Then, there are debates surrounding the efficacy and reliability of the tests and their ability to corroborate results. For example, a review of prediabetes found evidence of poor correlation between A1C, IFG and IGT results.

Controversy Surrounding the HbA1C Test

The HbA1C test has come under particular scrutiny. This study in the American Journal of Medical Sciences found that the HbA1C test was poor at predicting prediabetes and that clinicians should refer patients for additional oral glucose testing.

Other findings suggest a strong genetic component in HbA1C, concluding that it’s inherently imprecise. Similarly, another study in Metabolic Syndrome and Related Disorders concluded: “It is important to consider that HbA1c values below 6.5% (for diabetes) and 5.7% (for prediabetes) do not reliably exclude the presence of diabetes and prediabetes, respectively.”

Since the A1C test measures glycated hemoglobin (HbA1c), it’s vulnerable to a myriad of factors affecting HbA1c lifespan and function.

Adding another twist to the debate is a study published in March 2023 which found that the HbA1c test was superior to the IFG (impaired fasting glucose) test for predicting severe diabetic complications, in this case adverse cardiovascular outcomes, in vulnerable individuals.

Contradictions in the Literature

To further salt the wound, evidence surrounding the testing and diagnosis of prediabetes is often contradictory.

● For example, this study from the American Journal of Hypertension says: “The combination of FPG and HbA1c is a reasonable alternative to the generally recommended OGTT for the screening of diabetes”. The authors found the use of the OGTT as the gold standard warrants skepticism.

● Whereas, this one in the American Journal of Medical Science says, “Patients with HbA1c of 5.7% to 6.4% should undergo OGTT to confirm diagnosis of dysglycemia.” The authors reinforce the OGTT as the gold standard.

IGT and IFG are also affected by those who are hypoglycemic, anemic, exhibit altered hematocrit (percentage of red blood cells in the blood), and hypotensive. As such, this study published in Clinical Chemistry and Laboratory Medicine found poor replicability for both of these tests, advising caution for interpreting a single test result.

To further muddy the waters, test conditions are highly influenceable. For example, we know that, for example, eating dinner early improves 24-hour blood glucose levels. Fasting overnight after eating salads all day is likely more favorable for a fasting glucose test than fasting overnight after consuming sodas and fast food all day.

Hormones concentrations in the morning, the “Dawn Phenomenon,” can also affect test results, particularly in those with hormonal conditions. The Dawn Phenomenon is a normal hormonal reflex which increases blood sugar levels in the early morning. For most, this peaks around 3 am to 4 am, but it can extend to 8 am for some, which may feasibly impact glucose test results.

Moreover, diabetes tests often use subsidized rapid test strips with short expiry dates. They’re also affected by variables like temperature, humidity, and quality of blood samples, with error rates of around 12 to 15% in some cases.

In summary, the evidence suggests prediabetes diagnosis is highly sensitive to diagnostic and individual factors.

A review of prediabetes published in the World Journal of Diabetes concludes, to this effect, “the criteria used to define prediabetes needs to be refined in accordance to the long-term medical outcomes.”

Prediabetes Diagnosis: An Opportunity for Positive Change?

Prediabetes screening and diagnosis are becoming more common worldwide, but this presents new challenges for clinicians and health management.

For example, in the UK, the national rollout of the new Diabetes Prevention Programme (DPP) has vastly increased the number of people diagnosed with prediabetes. Clinicians are now raising concerns about the tests and criteria used to define prediabetes and also the social ramifications of creating a ‘new disease’ that may cause depression, anxiety, and stigma.

Harnessing prediabetes diagnosis for positive change is essential. That includes establishing clear guidelines for testing, effectively communicating results with patients, and establishing personalized treatment strategies.

Among all of this, there is at least one positive thing about prediabetes: it’s reversible.

Lifestyle changes such as diet and exercise can reduce risk by 40% to 70% or more, with the added bonus of reducing risk factors for numerous other diseases and disorders.

Stay tuned for our next article to learn about changing the course of prediabetes.

Can Actos Really Prevent Type 2 Diabetes?

Diagnosing diabetes is simple. If the blood sugar is found to be elevated you are diabetic. Increasing or decreasing the cut off level between normal and diabetic will dramatically change the number of people diagnosed with diabetes. In 1997 the American Diabetes Association lowered the criterion of diabetes (type 2) to a fasting blood sugar above 126 mg/dl instead of 140 mg/dl. Suddenly 1.7 million Americans became “diabetic” under the new definition.

In the latest issue (March 24, 2011) of the New England Journal of Medicine research was published stating that Actos (pioglitazone), a popular medication used to treat type 2 diabetes, could substantially reduce the percentage of people at high risk for developing diabetes who progress to actual diabetes. 600 people with a form of pre-diabetes known as impaired fasting blood sugar (fasting blood sugar levels between 95 and 125), were divided into one group given placebo and the other group given Actos. After 2.5 years Actos reduced the incidence of developing type 2 diabetes by 72% compared to placebo. Initially, I was very impressed with these results.

Actos is the sister drug to Avandia and Rezulin. All of these drugs show similar ability to reduce blood sugar in diabetics. Rezulin and Avandia fell into disfavor due to the potential for side effects. Actos is considered safer.

It seems almost a little too obvious that if diabetes is defined as elevated blood sugar that if the test medication reduces blood sugar, diabetes can be “prevented”. Since Actos lowers blood sugar, the conclusion that Actos reduces the progression of pre-diabetes to actual diabetes seems inevitable. A substance that does not already lower blood sugar which prevented elevated blood sugar from developing would be far more impressive.

Side-effects of taking Actos need to be considered, as well. In this research study (New England J of Medicine 364; 12, 2011) the group taking Actos gained an average of about 9 pounds. That doesn’t include the 3% of test subjects who dropped out of the study because they gained too much weight. Edema (puffy ankles) was also more common in those taking Actos. We know that weight gain, particularly in pre-diabetics, is not a good thing. What are we hoping to accomplish by using Actos to prevent diabetes when at the same time, we make people chunkier and puffier?

To be fair, the family of medications known as “glitazones” which contain Actos, Avandia and Rezulin, have some intriguing properties. Years ago, the Triad Study, showed that women with gestational diabetes who received Rezulin, did not go on to develop type 2 diabetes nearly as often, even years after stopping this medication. This does seem like a true preventive benefit.

I am dubious about using Actos to prevent diabetes at this time. My patients, I suspect, will agree with that decision. I don’t think I would survive very long in practice, if my patients gain 10 or more pounds as I try to “prevent” their progression to diabetes.

This information is for educational purposes only and is not intended as medical advise or treatment. Always consult with your physician when deciding whether to use a prescription drug.

Gary Pepper, M.D.

Editor-in-Chief, Metabolism.com

Verified by MonsterInsights