Prediabetic states : IFG and IGT

"Prediabetes" is a term used to describe a condition of altered glucose metabolism which falls short of a formal definition of diabetes yet confers an increased risk of progression to diabetes and/or vascular disease. The word itself has been used intermittently for most of a century, reflecting contemporary notions of diabetes, and remains controversial. Modern understanding began with the 1980 definition of diabetes which recognised the category of impaired glucose tolerance (IGT) as intermediate between diabetes and normoglycaemia, and associated with an increased risk of cardiovascular events. Since IGT could only be diagnosed by OGTT, it had limited clinical application until the introduction of a single impaired fasting glucose (IFG) criterion by the ADA in 1997; the term prediabetes was reintroduced in the USA at that time. An HbA1c criterion for prediabetes was subsequently introduced, allowing three different routes to diagnosis. This move drastically increased the number of people considered at risk, for example to 76 million in the USA. Although these criteria are widely incorporated into national guidelines, there are concerns related to poor correlation between the three diagnostic measures, lack of evidence as to the benefits of intervention, and the potential unwanted effects of creating a new disease entity.

Introduction

Diabetes was originally defined by symptoms and glycosuria, but the introduction of simple blood tests for glucose extended the definition to asymptomatic individuals with hyperglycaemia but no glucose in their urine. Elliot Joslin (1870-1962) referred to this as potential diabetes, and defined it as a fasting blood glucose above the normal range but below his personal cut-off for diabetes of 7.8 mmol/L (140 mg/dl).

As blood tests became more widely used, the phenomenon of asymptomatic hyperglycaemia attracted greater interest. This was generally recognised as a precursor to overt diabetes but was not considered worth treating. This remained the case until the introduction of the sulfonylureas in the 1950s simplified its management [1].

"Prediabetes" first entered the diabetes lexicon in 1933 when Tyner performed glucose tolerance tests (according to contemporary criteria) in obese individuals with and without a family history of diabetes, and found that the latter were more likely to have an abnormal test. The early history of the concept is discussed in the section entitled Prehistory of prediabetes.

Other states conferring an increased risk of diabetes were also recognised. These included obesity, a family history of diabetes, and gestational diabetes and/or delivery of big babies.

Defining diabetes

Little understanding of states bordering on diabetes could be reached in the absence of an agreed definition of diabetes itself. It was generally believed that those with diabetes represented a genetically distinct subgroup within the population as a whole, and one big question, relating to a range of conditions including hypertension as well as diabetes, was whether it was possible to draw a clear line between those with disease and those without.

It was assumed that diabetes was a genetic trait. Since no genetic marker was available, metabolic physicians made many attempts to define the phenotype of the condition in terms of glucose abnormalities. Challenge tests, such as the steroid-augmented OGTT, were used to pursue metabolic traits predictive of diabetes. The insulin radioimmunoassay was also used in the attempt to identify diagnostic patterns of insulin secretion, but no clear dividing line could be drawn between those with diabetes and those without.

The epidemiologists, meanwhile, looked to see whether the diseased and non-diseased groups fell within the same statistical distribution. The expectation was that a genetically distinct population would diverge from the healthy population with increasing age to reveal a bimodal distribution with two distinct peaks. Some populations, such as the Pima Indians, appeared to show this pattern, but the overall picture was of a single distribution, skewed towards the higher glucose values and showing a progressive right shift with increasing age.

Last but not least, a formal definition of diabetes was still lacking. Attempts were made to solve the problem with the help of expert advice, but it rapidly emerged that experts differed wildly in their opinion as to the threshold for diagnosing diabetes.

The epidemiologists define diabetes

The epidemiologists now came into their own. It was clear that no definition of diabetes and intermediate states of glucose tolerance could be reached while there was (1) lack of an agreed diagnostic test, and (2) uncertainty as to the prognostic implications of hyperglycaemia.

Breakthrough came in 1980 when an expert group of WHO, guided by Harry Keen and Kelly West (1925-1980) endorsed a prognostic definition of diabetes, based upon prospective studies of outcomes in populations with a baseline OGTT. The risk of diabetic retinopathy showed an upward deflection in those whose 2-hour plasma glucose exceeded 11.1 mmol/l (200 mg/dl), a finding confirmed in different populations around the world.

The committee then looked at those whose glucose values were “intermediate between normal and diabetic”, and these were now said to have impaired glucose tolerance (IGT). Previous terminology including prediabetes was explicitly discarded. IGT was considered a heterogeneous entity, not least because of the poor reproducibility of the OGTT, but carried an increased risk of arterial disease and progression to diabetes. It was defined by an OGTT with a fasting plasma glucose value below 7.8 mmol/l (140 mg/dl), and a 2-hr value between 7.8 – 11.1 mmol/l (140 – 200 mg/dl). No advice was offered concerning screening or management for a condition that arose exclusively as a by-product of the OGTT, and whose prognostic implications were far from certain.

Two thresholds for glycaemic risk

Hyperglycaemia, as defined by the OGTT, now had two cut-off points: a disease threshold based upon risk of retinopathy, and a lower threshold denoting increased risk of cardiovascular disease or diabetes. The former has never seriously been questioned. In contrast, cardiovascular risk is continuously distributed, has many determinants other than glucose, and has not been shown to respond to glucose lowering therapy. No surprise, therefore, that the glucose cut-off for macrovascular risk has given rise to unending controversy.

In 1997 the ADA Expert Committee on the Diagnosis and Classification of Diabetes met to reconsider the diagnosis and classification of diabetes, and proposed that the time consuming, costly and poorly reproducible OGTT should be replaced by a simple test of fasting plasma glucose, which correlates almost equally well with risk of retinopathy. The fasting threshold for diabetes was then lowered to 7 mmol/l (126 mg/dl), and the upper threshold of normality was set at 6.1 mmol (110 mg/dl), creating the new diagnostic entity of Impaired Fasting Glucose (IFG). In 2003 the Expert Committee opted to lower the fasting glucose threshold for IFG to 5.6 mmol/l (100 mg/dl).

Implications of the new criteria

Although endorsed by leading bodies of opinion such as the ADA and NICE, the new criteria and terminology are not universally accepted. Many people object to the use of the word "prediabetes" as inaccurate (many of those so designated will never develop diabetes) and stigmatizing. Proponents of the term counter with the argument that this approach is a great incentive to behaviour change.

In practice, the word itself is more widely favoured in the USA, and the terminology remains unstandardized. IGT and IFG are defined categories, but no universal usage has been developed to encompass people who have IGT or IFG or raised HbA1c. "Impaired glucose regulation" is one suggestion.

A further concern was that IGT was found in 751 individuals in one study population at a cut-off level of 6.1 mmol/l (110 mg/dl), as against 520 people with IFG; only 219 (17%) tested possible on both measures. At the lower fasting threshold of 5.6mmol/l 100 mg/dl), 2356 people now had IFG, as against 751 with IGT, and only 449 (still 17%) were positive by both tests. The authors considered that lowering the diagnostic threshold had the effect of creating a “pandemic of prediabetes” [2]. Increasing the sensitivity of the test, as the authors point out, greatly reduces its specificity, increasing the number of false positives.

Efficiency of diabetes prediction

Recent analysis shows that the cumulative progression rate to diabetes is lowest for those with HbA1c 6.0-6.4% and highest in those with IFG plus IGT; see Table [3].

Table 1: Cumulative incidence rate of diabetes with different criteria for prediabetes rate per 100 patient years [95% credible interval]

Criterion rate/1000 95% credible interval
HbA1c 6.0-6-4% 35.6 [15.1, 83.0]
FPG >5.6 nM (100mg/dl) 35.5 [26.6, 48.0]
FPG >6.1 mM (110 mg/dl) 47.4 [37.4, 54.5]
IGT 45.5 [37.8, 54.5]
IGT + IFG 70.4 [53.8, 89.7]

Efficiency of CVD prediction

The two main rationales for diagnosing prediabetes are prevention of diabetes itself and of the associated cardiovascular disease. Many studies have shown that people with abnormal glucose metabolism are at increased cardiovascular risk, but the excess risk is not great. One frequently cited systematic review found a relative risk (RR) of 1.20 [95% CI 1.12-1.28] for 18 studies based upon IFG (diagnostic threshold BG >6.1 mM (110 mg/dl), and a RR of 1.10 [95% CI 0.99-1.23] for those with both IFG and IGT (5 studies) [4]

A bogus category?

Opinion is still sharply divided between proponents and opponents of prediabetes. Proponents argue that it is never too early to intervene to prevent or delay the onset of diabetes and its associated cardiovascular risks. Opponents point to the lack of agreement between different definitions of dysglycaemia and to the large number of false positives generated. Proponents will argue back that the stimulus provided by a diagnosis of prediabetes will encourage healthy behaviours, which are useful regardless of progression to diabetes itself. Opponents will counter with the stigmatizing implications of the diagnosis, the generation of unwarranted anxiety, and the increased likelihood of unwarranted pharmacotherapy. And so forth.

From a more objective point of view, there are the following concerns:

  1. Does treatment of prediabetes alter the natural history of the disease process - or is it simply earlier treatment for hyperglycaemia?
  2. How relevant are the intervention trials for prediabetes? These mostly used IGT (confirmed in two tests) as the entry criterion, not the current splay of diagnostic criteria. Further, they targeted a younger age group than the elderly who make up the bulk of prediabetes.
  3. How useful is the treatment? Lowering blood glucose is not a very effective cardiovascular preventive measure in established diabetes, and has not been shown to be useful in prediabetes.
  4. Is it worth screening for prediabetes? Most authorities feel that routine screening for diabetes is unjustified, which questions the logical basis of screening for a condition that precedes diabetes.
  5. There seems little doubt that the drive to diagnose and treat prediabetes is driven in part by professional organizations anxious to emphasise the importance of diabetes and the number of people at risk - but is this a legitimate basis for medical intervention?

Readers are referred to the article by Yudkin and Montori [5] for an up-to-date and critical review of the topic.

The text of successive WHO statements can be found at:

WHO 1: http://whqlibdoc.who.int/trs/WHO_TRS_310.pdf

WHO 2: http://whqlibdoc.who.int/trs/WHO_TRS_646.pdf

References

  1. ^ Greene JA. Prescribing by numbers. Drugs and the definition of disease. Johns Hopkins, Baltimore, 2007

  2. ^ Borch-Johnsen K et al. Creating a pandemic of prediabetes: the proposed new diagnostic criteria for impaired fasting glucose. Diabetologia 2004;47:1396-1402.

  3. ^ Morris DH et al. Progression rates from HbA1c 6.0-6.4% and other prediabetes definitions to type 2 diabetes: a meta-analysis. Diabetologia 2013;56:1489-1493

  4. ^ Ford ES et al. Prediabetes and the risk for cardiovascular disease: a systematic review of the evidence. JACC 2010;55:1310-17

  5. ^ Yudkin JS, Montori V. The epidemic of prediabetes: the medicine and the politics. BMJ 2014 Jul 15;349:g4485.

Comments

  1. Gauranga Dhar
    Gauranga Dhar added a compliment on 2 October 2014 at 02:57PM
    First of all I thank author E.A.M. Gale for this nice article on pre-diabetes. On “A bogus category?” I got opinions of both proponents and opponents.
    According to my opinion “pre-diabetes” is an established condition and there should not be any debate on this terminology in this era. As type 2 diabetes is skyrocketing all over the world, pre-diabetes can be considered as “iceberg phenomenon” in the branch of Diabetology.
    Family/Primary care physicians should get a good idea both on screening and follow-ups of pre-diabetes to prevent serious epidemics of micro and macrovascular complications associated with not only in overt type 2 diabetes but in pre-diabetic stages as well.
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