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.

Are New Diabetes Medications Worth the Money?

(I don’t think so, and here’s why.)

The FDA just announced its approval of linagliptin (Tradjenta), a new diabetes medication developed by Eli Lilly and Company and Boehringer Inglheim. Linagliptin is the third drug to be approved in the class of medications commonly known as gliptins (scientifically known as dipeptidyl peptidase-4 (DPP-4) inhibitors) which block the destruction of a glucose controlling hormone, GLP-1. Januvia, developed by Merck and Company, was the first of the gliptins to be approved in 2006. Three years later in 2009, Onglyza, developed by AstraZeneca was approved while two other similar drugs were withdrawn from the approval process in the meantime.

Diabetes drugs are evaluated by the FDA for safety and for their ability to combat diabetes by lowering blood sugar. Assuming the drug being evaluated is safe then we will want to know how effectively the new medicine lowers the blood sugar. The glycohemoglobin A1c blood test represents the average blood sugar for the prior 3 months, and is the most concise way of assessing an individuals over all blood sugar control. By determining the ability of a medicine to lower the “glycoA1c” we can get a very accurate idea of the strength of the medicine for diabetes treatment. In general, physicians set a glycoA1c goal of 7% or less for their diabetic patients which equates to an average blood sugar level of 154 mg/dl or 8.6 mmol/L.

Linagliptin passed the FDA’s strigent safety review. Several large studies sponsored by the drug developers show the linagliptin lowers glycohemoglobin A1c by about 0.5. For example, if a person has a glycoA1c of 7.5 % before starting linagliptin, they can anticipate it will be 7.0% when on the medication. This translates to an average blood sugar of 169 mg/dl dropping to 154. This is virtually the same effect found with Januvia and Onglyza, the other medicines in this group.This amount of blood sugar lowering seems feeble but the benefit is even worse then that. Here’s why.

Blood tests are accurate enough for the clinical purposes of physician’s diagnosing and treating their patients. “Clinical purposes” allow for some fuzziness in measurements. Does it matter to a patient’s health if the blood sugar is 200 or 210? Not really. In general, a variation of 10% is acceptable for clinical blood tests, meaning that if a result is given as 100, a repeat measurement of the same blood sample could read between 95 and 105. For the glycohemoglobin A1c test a variation of 0.5 is common with standard laboratory techniques. For an individual on linagliptin there is virtually no way to determine if the change in glycoA1c is due to the medication or is simply within the variation of the blood test. Not very impressive is it?

How much is the average person going to pay for this unimpressive effect? I researched the retail cost of Januvia, the sister drug to linagliptin. Drugstore.com lists a price of $216 for 30 pills after a 18% saving. $7 per pill….wow!! I assume linagliptin will be priced competitively. Compare this to the price of $13 for a month’s supply of metformin, currently the most prescribed oral agent for treating diabetes. In contrast, metformin shows a 1.5% to 2% drop in glycohemoglobin A1c, more than three times that of the gliptins such as linagliptin.

I have used both Januvia and Onglyza in my medical practice. As advertised, I haven’t encountered significant side effects. Also, as advertised the effect of these medicines to lower blood sugar has been disappointing and complaints by patients about the cost has been a constant theme. At the same time my email inbox is stuffed with invitations to join online symposiums with paid experts inevitably focusing on how to ramp up my use of these drugs. The sales pitch is given in inflated marketing lingo as a “change in the treatment paradigm” for treating diabetes. Buyer beware, is my advice for the health care consumer starting a new medication for treating type 2 diabetes.

Gary Pepper, M.D.
Editor-in-Chief, metabolism.com

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