https://orcid.org/0000-0001-6141-634X
Abstract
With the increasing burden of diabetes as a cause of macro- and microvascular disease linked to the epidemics of obesity, attention is being paid to dysglycaemic states that predict and precede the development of type 2 diabetes. Such conditions, termed pre-diabetes, are characterized by fasting plasma glucose, or plasma glucose levels on an oral glucose tolerance test, or values of glycated haemoglobin intermediate between ‘normal’ values and those characterizing diabetes. These last are by definition associated, in epidemiological terms, with a higher incidence of microvascular disease—mostly retinopathy. Pre-diabetes overlaps with the components of the ‘metabolic syndrome’—among which are excess visceral adiposity; hypertension; hypertriglyceridaemia; high levels of small, dense low-density lipoproteins; and metabolic-associated fatty liver disease. There is little doubt that pre-diabetes has important prognostic implications, especially for the occurrence of myocardial infarction, ischaemic stroke, and peripheral arterial disease. It is disputed, however, whether pre-diabetes is itself an actionable disease entity, in addition to the risk factors characterizing it. Because of this uncertainty, the latest European Society of Cardiology guidelines chose not to include pre-diabetes as a treatment target for atherosclerotic cardiovascular disease, at variance from the three previous editions of such guidelines. This is spurring a debate, the Pro and Contra arguments featured in the present debate article.
A schematic representation of the time course of development of type 2 diabetes in the context of excess calorie intake. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) occur years before blood glucose exceeds the so-called diabetic threshold, above which microangiopathy starts to occur and type 2 diabetes is diagnosed. Much before the diagnosis of diabetes, however, the progressive decline in insulin sensitivity and initially compensatory insulin hypersecretion lead to the earlier occurrence of macroangiopathy (large vessel atherosclerosis) and the development of atherosclerotic vascular disease (circled in red). The time frame of IFG, higher-than-normal glycated haemoglobin (HbA1c), and, probably more relevant, IGT revealed at the oral glucose tolerance test (OGTT) is termed ‘pre-diabetes’. Whether pre-diabetes is an actionable target for interventions, independent of risk factors common to all vascular disease, is debated. CV, cardiovascular
Introduction
Diabetes mellitus (DM), mostly type 2 (T2DM), is a well-recognized dreadful cause of morbidity and mortality worldwide, being a major cause of heart attacks, stroke, lower limb amputation, blindness, and kidney failure. The World Health Organization (WHO) reported that the number of people with diabetes has quadrupled from 108 million in 1980 to 422 million in 2014 and now keeps increasing with the wider prevalence of overweight and obesity (https://www.who.int/news-room/fact-sheets/detail/diabetes). Prevalence and mortality have been rising more rapidly in low- and middle-income countries. Here, mortality by age due to diabetes increased 13% between 2000 and 2019, compared with an overall 3% increase in high-income countries. In 2019, diabetes and kidney disease due to diabetes caused an estimated 2 million deaths worldwide.1
The huge impact of diabetes on human health demands adequate preventive and therapeutic measures. Besides treating diabetes, attention has also been logically focusing on conditions predisposing to and preceding diabetes, which may themselves be the target of lifestyle and therapeutic interventions. Such conditions, involving glycaemic control out of normality ranges but below the glycaemic thresholds, precede and predict the occurrence of diabetes and mark a higher risk of cardiovascular disease.
Like most biologic phenomena, defining a precise ‘threshold’ to diagnose a disease is somewhat artificial. Diabetes itself is now diagnosed on the basis of fasting plasma glucose (FPG), or random plasma glucose, or glycated haemoglobin (HbA1c), or the glycaemic response to an oral glucose load, in the so-called oral glucose tolerance test (OGTT). Such threshold values are reported in Table 1.2
Biochemical diagnostic criteria for diabetes and pre-diabetes according to the World Health Organization and the American Diabetes Association (from ref. Marx et al.2)
| Glycaemic maker | WHO criteria (2011, 2019) | ADA criteria (2021) |
|---|---|---|
| Diabetes | ||
| FPG | ≥7.0 mmol/L (≥126 mg/dL) | |
| 2hPG | ≥11.1 mmol/L (≥200 mg/dL) | |
| HbA1c | >6.5% (>48 mmol?mol) | |
| RPG | ≥11.1 mmol/L (≥200 mg/dL) | |
| Glycaemic maker | WHO criteria (2011, 2019) | ADA criteria (2021) |
|---|---|---|
| Diabetes | ||
| FPG | ≥7.0 mmol/L (≥126 mg/dL) | |
| 2hPG | ≥11.1 mmol/L (≥200 mg/dL) | |
| HbA1c | >6.5% (>48 mmol?mol) | |
| RPG | ≥11.1 mmol/L (≥200 mg/dL) | |
| Pre-diabetes | ||
|---|---|---|
| FPG | 6.1–6.9 mmol/L (110–125 mg/dL) | 5.6–6.9 mmol/L (100–125 mg/dL) |
| 2hPG (OGTT) | 7.8–11.0 mmol/L (140–199 mg/dL) | |
| HbA1c | 6.0%–6.4% (42–47 mmol/mol) | 5.7%–6.4% (39–47 mmol/mol) |
| Pre-diabetes | ||
|---|---|---|
| FPG | 6.1–6.9 mmol/L (110–125 mg/dL) | 5.6–6.9 mmol/L (100–125 mg/dL) |
| 2hPG (OGTT) | 7.8–11.0 mmol/L (140–199 mg/dL) | |
| HbA1c | 6.0%–6.4% (42–47 mmol/mol) | 5.7%–6.4% (39–47 mmol/mol) |
ADA, American Diabetes Association; 2hPG, 2 h plasma glucose; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; RPG, random plasma glucose; OGTT, oral glucose tolerance test; WHO, World Health Organization.
Biochemical diagnostic criteria for diabetes and pre-diabetes according to the World Health Organization and the American Diabetes Association (from ref. Marx et al.2)
| Glycaemic maker | WHO criteria (2011, 2019) | ADA criteria (2021) |
|---|---|---|
| Diabetes | ||
| FPG | ≥7.0 mmol/L (≥126 mg/dL) | |
| 2hPG | ≥11.1 mmol/L (≥200 mg/dL) | |
| HbA1c | >6.5% (>48 mmol?mol) | |
| RPG | ≥11.1 mmol/L (≥200 mg/dL) | |
| Glycaemic maker | WHO criteria (2011, 2019) | ADA criteria (2021) |
|---|---|---|
| Diabetes | ||
| FPG | ≥7.0 mmol/L (≥126 mg/dL) | |
| 2hPG | ≥11.1 mmol/L (≥200 mg/dL) | |
| HbA1c | >6.5% (>48 mmol?mol) | |
| RPG | ≥11.1 mmol/L (≥200 mg/dL) | |
| Pre-diabetes | ||
|---|---|---|
| FPG | 6.1–6.9 mmol/L (110–125 mg/dL) | 5.6–6.9 mmol/L (100–125 mg/dL) |
| 2hPG (OGTT) | 7.8–11.0 mmol/L (140–199 mg/dL) | |
| HbA1c | 6.0%–6.4% (42–47 mmol/mol) | 5.7%–6.4% (39–47 mmol/mol) |
| Pre-diabetes | ||
|---|---|---|
| FPG | 6.1–6.9 mmol/L (110–125 mg/dL) | 5.6–6.9 mmol/L (100–125 mg/dL) |
| 2hPG (OGTT) | 7.8–11.0 mmol/L (140–199 mg/dL) | |
| HbA1c | 6.0%–6.4% (42–47 mmol/mol) | 5.7%–6.4% (39–47 mmol/mol) |
ADA, American Diabetes Association; 2hPG, 2 h plasma glucose; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; RPG, random plasma glucose; OGTT, oral glucose tolerance test; WHO, World Health Organization.
Such values were defined as those at which there starts to be evidence of accompanying or ensuing microvascular disease, mostly retinopathy and, to a lesser extent, (micro)albuminuria.3,4 There has been convincing evidence, however, that, in individuals later developing diabetes, macrovascular (atherosclerotic) disease—leading to myocardial infarction, ischaemic stroke, and peripheral arterial disease—begins years before and parallels the gradual development of insulin resistance and decreased pancreatic beta-cell function.5–7 This has been termed as ‘the ticking clock hypothesis’, with the concept that the clock starts ticking years before the onset of clinical diabetes.6 This occurs especially in the context of a cluster of alterations, including high blood pressure; metabolic-associated fatty liver disease (previously defined as non-alcoholic fatty liver disease); hypertriglyceridaemia; increased levels of small, dense, low-density lipoproteins; and the polycystic ovary syndrome, all very often preceded by excess body weight and visceral fat deposition, and all having in common a progressively increased insulin resistance, the so-called metabolic syndrome.8 A graphical representation of the much earlier time of onset of macrovascular compared with microvascular disease, mostly in the context of excess adiposity, is presented in the Graphical abstract.
This being the case, a logical step in preventing macrovascular complications and the very same onset of T2DM would be an earlier diagnosis of conditions preceding the onset of diabetes, conditions termed ‘pre-diabetes’. These can be unmasked by levels of plasma glucose, or HbA1c, or post-load plasma glucose at the OGTT intermediate between ‘normal’ values and those characterizing full-blown diabetes. The WHO and the American Diabetes Association (ADA) have issued slightly different definitions of pre-diabetes (Table 1), with more lenient definitions proposed by the ADA. According to the latter, a person with a FPG ≥ 100 mg/dL, an HbA1c ≥ 5.7% (39 mmol/mol), and a 2 h plasma glucose at the OGTT ≥ 140 mg/dL and not qualifying as ‘diabetes’ would qualify as pre-diabetes.
Diagnosing pre-diabetes, not only diabetes, is already known to have important prognostic implications but has to be actively pursued. While FPG and HbA1c are routinely measured at hospital entry for an acute coronary syndrome (ACS), the performance of the OGTT entails a bit more of organization. Yet, its diagnostic yield has been reported as remarkable: when performed in the setting of an ACS, usually at hospital discharge, patients identified as with impaired glucose tolerance (IGT) or T2DM had clearly a worse outcome than patients with normal glucose tolerance.9 In the Glucose Tolerance in Patients with Acute Myocardial Infarction (GAMI) trial, both such groups of patients had an outcome in terms of major adverse cardiovascular events (MACEs: death, myocardial infarction, or stroke) clearly worse than patients with normal glucose tolerance, normal FPG, and normal HbA1c. Actually most MACEs in the follow-up of these patients clustered in patients with dysglycaemia.10 Importantly—and contrary to a widely held previous belief—IGT was not related to the surge of contra-insular hormones accompanying the ACS, but was stable over time in the follow-up.11 Results on the yield of the OGTT in the acute setting have not all, however, been totally consistent.12 Recent data have also led to the proposal of using the easier-to-perform and more convenient 1 h OGTT, as a substitute for the ‘classical’ 2 h OGTT,13 and this position has been very recently endorsed by the International Diabetes Federation (IDF) with the setting of new criteria for pre-diabetes, as shown in Table 2.
New diagnostic criteria of plasma glucose values proposed by the International Diabetes Federation for diagnosing pre-diabetes with the 1 h oral glucose tolerance test (OGTT; https://idf.org/news/idf-position-statement-1-hour-pg-test/)
| Normal | Pre-diabetes | Diabetes | |
|---|---|---|---|
| OGTT (1 h) | ≤154 mg/dL | 155–208 mg/dL | ≥209 mg(dL) |
| ≤8.6 mmol/L | 8.6–11.6 mmol/L | ≥11.6 mmol/L |
| Normal | Pre-diabetes | Diabetes | |
|---|---|---|---|
| OGTT (1 h) | ≤154 mg/dL | 155–208 mg/dL | ≥209 mg(dL) |
| ≤8.6 mmol/L | 8.6–11.6 mmol/L | ≥11.6 mmol/L |
New diagnostic criteria of plasma glucose values proposed by the International Diabetes Federation for diagnosing pre-diabetes with the 1 h oral glucose tolerance test (OGTT; https://idf.org/news/idf-position-statement-1-hour-pg-test/)
| Normal | Pre-diabetes | Diabetes | |
|---|---|---|---|
| OGTT (1 h) | ≤154 mg/dL | 155–208 mg/dL | ≥209 mg(dL) |
| ≤8.6 mmol/L | 8.6–11.6 mmol/L | ≥11.6 mmol/L |
| Normal | Pre-diabetes | Diabetes | |
|---|---|---|---|
| OGTT (1 h) | ≤154 mg/dL | 155–208 mg/dL | ≥209 mg(dL) |
| ≤8.6 mmol/L | 8.6–11.6 mmol/L | ≥11.6 mmol/L |
In our own experience, on the basis of 192 consecutive ACS patients not previously known as having diabetes and investigated with an OGTT before discharge, only those with both 1 h plasma glucose ≥ 155 mg/dL and 2 h plasma glucose ≥ 140 mg/dL had more severe myocardial injury and longer hospitalization, confirming the important role of the 1 h plasma glucose OGTT in contributing to assessing post-ACS cardiac risk, but also showing an additive, and thus complementary, role of the 2 h plasma glucose in specifically identifying patients at a higher cardiovascular risk.14
But is pre-diabetes an independent pathological entity, configuring an actionable target, or is it only the clustering of cardiovascular risk factors, already individually targeted? Is pre-diabetes the frontier for new treatments?
Here, opinions diverge. The latest ESC Guidelines on diabetes2 chose not to include pre-diabetes as a treatment target, at variance from two previous versions of such guidelines, because of the debatable yield and convenience of the OGTT in the acute setting and of the poor additional actionability of pre-diabetes once diagnosed. This decision, clearly at variance from the recent statement of the IDF on the importance of the OGTT ((https://idf.org/news/idf-position-statement-1-hour-pg-test/), is spurring a debate.
The EHJ Editorial Board thus decided to accommodate this controversy in the Great Debates series, whereby main actors in the latest diabetes guidelines defend their choice, and a group of antagonists dispute it, trying to answer the crucial question: Is pre-diabetes an evidence-based treatment target for cardiovascular risk reduction? Debates like this will inform the reader on a controversy in an area of cardiology and medicine in general that is at the true frontier of knowledge and with far-from-negligible theoretical and practical consequences.
Supplementary data
Supplementary data are not available at European Heart Journal online.
Declarations
Disclosure of Interest
R.D.C. declares having received fees, honoraria, and research funding from Sanofi-Aventis, Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Novartis, Merck, Portola, Roche, AstraZeneca, Menarini, Guidotti, Milestone, Amarin, Noventure, and Amgen, all outside of the present topic.
References
Pro
Corresponding author. Email: [email protected]
The current 2023 ESC Guidelines on the management of cardiovascular disease (CVD) in patients with diabetes focus on patients with manifested disease and not on pre-diabetes.1 Given the lack of clear evidence, the new guidelines did not consider the aspect of pre-diabetes, which is a change compared to the previous 2019 and 2013 ESC Guidelines on diabetes, pre-diabetes, and CVD.2,3
Pre-diabetes: why not considered in the new ESC diabetes guideline?
The decision to not include pre-diabetes was extensively and critically discussed in the Task Force. The consensual conclusion was based on the following clinical rationale:
Pre-diabetes is classified by an elevation of plasma glucose above the normal range but below that of diabetes. It can be defined by impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both, and it is recognized that the presence of IFG or IGT are associated with an elevated risk to develop type 2 diabetes mellitus (T2DM). Pre-diabetes per se is thus defined by altered glucose levels between normal levels and those of diabetes, but the underlying pathophysiological and metabolic alterations are similar to those occurring in patients with diabetes: overweight and obesity, altered fat distribution, metabolic dysfunction–associated fatty liver disease, high triglycerides, low-grade inflammation, and insulin resistance. The most important component leading to the conversion from pre-diabetes to diabetes is ß-cell dysfunction.
Pre-diabetes has only a minor impact on microvascular disease and some predictive value for the development of macrovascular disease, but most of this latter associations appear to be mediated through the metabolic syndrome and related features (Figure 1).4,5 Currently, the clinical approach to cardiovascular (CV) prevention in individuals with pre-diabetes is to treat all associated CV risk factors, as outlined in the respective ESC Guidelines, e.g. for hypertension or dyslipidaemias.6,7 In addition, preventive strategies, such as lifestyle intervention for individuals with elevated CV risk, like pre-diabetes, are outlined in the ESC Prevention Guidelines.8 However, in contrast to patients with diabetes, there is, so far, no dedicated CV outcome trial that has provided data on the reduction of CV events in patients with pre-diabetes. Thus, the main therapeutic strategy of this population is controlling risk factors and preventing the development of T2DM. This is in accordance with the 2019 and 2013 ESC Guidelines, which—although mentioning pre-diabetes in their title—provided no specific pre-diabetes recommendations besides those to prevent manifestation of T2DM. Therefore, the 2023 ESC Guidelines focused on evidence-based recommendations to manage CV risk and provided guidance for the treatment of CVD in patients with diabetes.
Pre-diabetes and its relations to type 2 diabetes and cardiovascular complications. There is no evidence that cardiovascular risk is directly mediated by pre-diabetes, but rather by the scenario (yellow bubbles) of frequently associated components of the metabolic syndrome, fat distribution, and inflammatory or other mediators. The background of these clusters of cardiovascular risk is the underlying insulin resistance, often related to overweight and obesity, as well as by the concert of organ-related kinins weaving a complex network of multi-organ crosstalk. The red arrows indicate relations to atherosclerotic cardiovascular disease risk; the solid arrow represents a relation stronger than for the empty arrow. ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; EAT, epicardial adipose tissue; HDL-C, high-density lipoprotein cholesterol; HF: heart failure; MAFLD: metabolic-associated fatty liver disease; MetS: metabolic syndrome; TG, triglyceride; T2DM: type 2 diabetes mellitus
Here, we will have a closer look at:
Pre-diabetes and atherosclerotic CVD (ASCVD) risk
Evidence for CV benefit by interventions in pre-diabetes.
Pre-diabetes and atherosclerotic cardiovascular disease risk
There is robust evidence that pre-diabetes is associated with an elevated CV risk, but the extent of risk increase is consistently not comparable to the risk occurring in patients with T2DM.9 A recent meta-analysis of 129 studies involving more than 10 million individuals demonstrated that pre-diabetes was associated with an increased risk of all-cause mortality [relative risk (RR) 1.13, 95% confidence interval (CI) 1.10–1.17], composite CVD (RR 1.15, 95% CI 1.11–1.18), coronary heart disease (RR 1.16, 95% CI 1.11–1.21), and stroke (RR 1.14, 95% CI 1.08–1.20) in the general population over a median follow-up of 9.8 years.10 Compared with normoglycaemia, the absolute risk difference in pre-diabetes for all-cause mortality, composite CVD, coronary heart disease, and stroke was 7.36% (95% CI 9.59–12.51), 8.75% (95% CI 6.41–10.49), 6.59% (95% CI 4.53–8.65), and 3.68% (95% CI 2.10–5.26) per 10 000 person-years, respectively. This corresponds to a higher absolute risk of <0.1% over a 10-year period (or 0.01% if rates are annually estimated). In patients with ASCVD, compared with normoglycaemia, pre-diabetes was associated with an absolute risk difference for all-cause death, composite CVD, coronary heart disease, and stroke by 66.19 (95% CI 38.60–99.25), 189.77 (95% CI 117.97–271.84), 40.62 (95% CI 5.42–78.53), and 8.54 (95% CI 32.43–61.45) per 10 000 person-years, respectively, corresponding to a higher absolute risk of <2% (indicating an annually increased incidence of less than 1%). A further systematic review and meta-analysis on pre-diabetes for predicting mortality, macrovascular, and microvascular outcomes identified 106 prospective studies, comprising nearly 1.85 million people from 27 countries, and demonstrated that IGT was associated with higher all-cause and CV mortality with a hazard ratio (HR) of 1.19 and 1.21, respectively.11 Impaired fasting glucose (110–125 mg/dL) was associated with a similarly elevated risk for all-cause mortality (HR 1.17) and CV mortality (HR 1.20). Glycated haemoglobin (HbA1c) in the range of 6.0%–6.4% was associated with an elevated CV risk with a HR of 1.32 and HbA1c 5.7%–6.4% levels with a HR of 1.15 (95% CI 1.02–1.30).
In the recently published CLEAR Outcomes trial, 13 970 patients were included, of whom 6373 (45.6%) with diabetes, 5796 (41.5%) with pre-diabetes, and 1801 (12.9%) with normoglycaemia.12 Over a median follow-up of 3.4 years, a graded relationship was observed for the incidence of the primary four-point major adverse cardiovascular event (MACE) endpoint, which was observed in 103 of 864 patients (11.9%) with normoglycaemia, 364 of 2885 patients (12.6%) with pre-diabetes, and 460 of 3229 patients (14.2%) with diabetes. These data demonstrate an absolute difference of only 0.7% in individuals with pre-diabetes compared with those with normoglycaemia, but a much more prominent 1.8% higher rate of CV outcomes in patients with diabetes compared with pre-diabetes, suggesting that the difference in risk was much more substantial in diabetes than in both pre-diabetes and normoglycaemia.
With respect to chronic heart failure (HF), there is no evidence that pre-diabetes per se is an independent risk factor for incident HF in older adults, while the associated risk factors (e.g. hypertension and obesity) are closely related to an elevated HF risk.13
In conclusion, based on the data of these studies with short- to mid-term follow-up, pre-diabetes defined by IGT, but not by IFG, appears to be associated with ∼30% elevation in the relative risk to develop CV events. This increase in risk is statistically significant, but lower than that in people with frank diabetes. This should be considered when one proposes to target patients with pre-diabetes as an evidence-based population for specific intervention measures.
Current evidence for diabetes and/or cardiovascular outcome prevention in pre-diabetes
More than a decade ago, Hopper investigated, in a large meta-analysis, whether treatment of individuals with IGT or IFG prevents or delays the onset of clinically overt diabetes, thus reducing major CV events or all-cause mortality.14 Trials included had to report all-cause death rates, and interventions for at least 1 year were divided into pharmacological and non-pharmacological. The prospective randomized controlled trials included in this analysis enrolled more than 23 000 patients with an average follow-up of 3.75 years. Overall, diabetes was delayed or prevented by interventions vs. control (risk ratio 0.83, 95% CI 0.80–0.86), and non-pharmacological approaches were superior to drug-based approaches in diabetes prevention (0.52, 95% CI 0.46–0.58 vs. 0.70, 95% CI 0.58–0.85, P < .05). However, there was no difference in all-cause mortality in the intervention vs. the control group (0.96, 95% CI 0.84–1.10), no difference in CV death (1.04, 95% CI 0.61–1.78), and only a non-significant trend towards a reduction in fatal and non-fatal myocardial infarction (0.59, 95% CI 0.23–1.50). Fatal and non-fatal stroke was borderline reduced (0.76, 95% CI 0.58–0.99) with intervention vs. control. Despite intervention strategies being mostly successful in preventing progression to overt diabetes, they did not result in reductions in all-cause or CV mortality, or myocardial infarction.
The Diabetes Prevention Program (DPP) focused on lifestyle intervention and metformin as strategies to prevent diabetes.15 Diabetes Prevention Program randomized 3234 persons without diabetes with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle modification programme with the goals of at least a 7% weight loss and at least 150 min of physical activity per week. With an average follow-up duration of 2.8 years, the incidence of diabetes per 100 person-years was 11.0 in the placebo group, 7.8 in the metformin group, and 4.8 in the lifestyle intervention group. Notably, the lifestyle intervention demonstrated a substantial 58% reduction in incidence (95% CI 48%–66%), while metformin exhibited a 31% reduction (95% CI 17%–43%) compared with the placebo group. Importantly, the lifestyle intervention proved to be significantly more effective than metformin in preventing the onset of diabetes.
The Da Qing IGT and Diabetes Study (Effects of Diet and Exercise in Preventing NIDDM in People With Impaired Glucose Tolerance) evaluated the impact of diet and exercise in preventing T2DM in 577 individuals with IGT.16 Individuals were randomly assigned to either a control group or one of three active treatment groups in a clinical trial: diet only, exercise only, or a combination of diet and exercise. Results revealed that, after 6 years, the cumulative incidence of diabetes was 67.7% (95% CI 59.8–75.2) in the control group, compared with 43.8% (95% CI 35.5–52.3) in the diet group, 41.1% (95% CI 33.4–49.4) in the exercise group, and 46.0% (95% CI 37.3–54.7) in the diet-plus-exercise group (P < .05).
The ACT-NOW study (Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance) randomized 602 adults with IGT to receive pioglitazone or placebo.17 The median follow-up period was 2.4 years. Pioglitazone reduced the risk of conversion of IGT to T2DM by 72% but was associated with significant weight gain and oedema.
The NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) study investigated the effects of nateglinide vs. placebo on the incidence of diabetes and CV events in 9306 participants with IGT and either CVD or CV risk factors.18 Over a median follow-up of 5 years, nateglinide, in comparison with placebo, did not exhibit a significant reduction in the cumulative incidence of diabetes (36% and 34%, respectively; HR 1.07; 95% CI 1.00–1.15; P = .05). Similarly, there were no significant differences observed in the composite CV outcome of death from CV causes, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for HF (7.9% and 8.3%, respectively; HR 0.94; 95% CI 0.82–1.09; P = .43). Even though nateglinide did not demonstrate CV benefits, it did elevate the risk of hypoglycaemia.
The STOP-NIDDM Trial (Study to Prevent Non-Insulin-Dependent Diabetes Mellitus) investigated the use of acarbose in preventing T2DM.19 Over a median follow-up of 3.3 years, administration of acarbose demonstrated notable benefits, including a 25% RR reduction in the onset of T2DM (HR 0.75; 95% CI 0.63–0.90; P = .0015). Furthermore, it contributed to a significant 34% reduction in the emergence of new cases of hypertension (HR 0.66; 95% CI 0.49–0.89; P = .0059) and a 49% reduction in the occurrence of CV events (HR 0.51; 95% CI 0.28–0.95; P = .03). However, CV event rate was very low, with 15 vs. 32 events mainly driven by myocardial infarction, with 1 vs. 12 events.
Lifestyle modification with weight loss has been shown to delay the progression from pre-diabetes to diabetes; a meta-analysis of 63 studies (n = 17 272) suggests that each additional kilogram loss was associated with 43% lower risk of T2DM.20
Furthermore, none of the interventions discussed above (with the exception of the hypothesis-generating trial with acarbose with a low number of events) could demonstrate a reduction in CV outcomes in individuals with pre-diabetes. Still, a recent international consensus concluded that dietary or lifestyle interventions can delay the progression to T2DM.21 However, there is large interindividual variability in response to preventive interventions. Identifying predictors of response to interventions and the characteristics of people who would most likely benefit remain the highest priority and will be a key focus for precision prevention in T2DM.
Conclusions
In conclusion, individuals with pre-diabetes exhibit an increased risk to develop overt diabetes and have a significantly elevated risk to develop CV events. Still, this increase in risk is lower than that in people with frank diabetes. Optimizing lifestyle habits and the respective interventions aimed at reducing risk factors should be implemented in pre-diabetes to prevent progression to clinically manifested diabetes; but so far there is no evidence that dedicated treatment strategies in these individuals with pre-diabetes reduce the risk of CV events. Lifestyle interventions for preventive measures, as well as risk factor control are all addressed in the ESC Prevention Guidelines.8 The aim of the recent 2023 ESC Guidelines on the management of CVD in patients with diabetes was to summarize the now robust evidence for specific clinical recommendations to reduce CV risk in patients with manifested diabetes. For all these reasons pre-diabetes was not included.1
Declarations
Disclosure of Interest
N.M. has given lectures for Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, and Novo Nordisk; has received unrestricted research grants from Boehringer Ingelheim; and has served as an advisor for Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, and Novo Nordisk. In addition, he served in trial leadership for Boehringer Ingelheim and Novo Nordisk. N.M. declines all personal compensation from pharma or device companies. N.M. is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TRR 219; Project-ID 322900939 [M03, M05]. D.M.-W. has acted as a consultant and has served on the speaker bureau for Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Lilly, Merck Sharp & Dohme, Novo Nordisk, and Sanofi. M.F. received unrestricted research grant by EFSD/Sanofi initiative; has given lectures for Novo Nordisk, Lilly & Co, Boehringer Ingelheim, Daiichi-Sankyo, Amgen, and Merck Sharp & Dohme; and has served as an advisor for Novo Nordisk, Lilly & Co, Boehringer Ingelheim, Amarin, Amgen, Merck Sharp & Dohme, and Organon; all fees were approved by the University of Rome Tor Vergata (Italian law n. 165/2001, art. 53). K.M-S.K.S. has received personal fees for lectures from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, MSD, Novo Nordisk, Novartis, and OmniaMed and served as an advisor for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, and Novo Nordisk. M.V. declares no competing interests. K.M.-S. is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TRR 219; Project-ID 322900939 [C07]).
References
Contra
Corresponding author. Tel: +46-707-292-171, Email: [email protected]
The first ESC Guidelines addressing diabetes, pre-diabetes, and cardiovascular disease were issued in 2007,1 and, to our knowledge, were the first on this issue. They were subsequently updated in 2013,2 2019,3 and 2023.4 This most recent update, labelled ‘2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes’,, included recommendations to use a new, type 2 diabetes mellitus (T2DM)–specific 10-year cardiovascular risk score (SCORE2-Diabetes) for people free from atherosclerotic or severe target-organ damage. It also strengthened recommendations to use cardioprotective glucose-lowering drugs (glucagon-like peptide-1 receptor agonists and/or sodium-glucose co-transporter 2 inhibitors) and paid particular attention to heart failure management. Of concern, however, is the omission of pre-diabetes in this update stated as follows: ‘The current Guidelines—in contrast to the previous Guidelines on diabetes, pre-diabetes, and cardiovascular diseases—only focus on cardiovascular disease and diabetes and, given the lack of clear evidence, leave aside the aspect of pre-diabetes’. Considering the increased cardiovascular risk of pre-diabetes and, in particular, of impaired glucose tolerance (IGT), the high risk of future T2DM in people with pre-diabetes, and the ability of lifestyle measures and of some drugs to prevent progression to T2DM and future cardiovascular outcomes, this omission may inadvertently reduce the potential to identify and optimize care for many people at high, lifetime risk of cardiovascular outcomes.
Plasma glucose: risk factor without an obvious threshold
Evidence that the risk of cardiovascular outcomes rises as a function of fasting plasma glucose (FPG), 2 h post-load glucose (2-hPG) during an oral glucose tolerance test (OGTT), and of levels of glycated haemoglobin (HbA1c) from euglycaemia through the pre-diabetes into the T2DM range strongly supports the importance of dysglycaemia, at least in the form of IGT, as a progressive cardiovascular risk factor.5–7 A large meta-analysis by Huang et al.8 that included 53 prospective cohort studies with 1 611 339 individuals followed during a median time of 9.5 years confirmed that the cardiovascular risk begins to rise above a FPG of 5.6 mmol/L. Notably, this meta-analysis did not differentiate between people who did and did not develop future T2DM. Moreover, as about 50% of the referenced studies did not include a 2-hPG from an OGTT, the authors could not differentiate between people with isolated elevated FPG and those who may also have had IGT or undiagnosed T2DM. Nevertheless, it illustrated the prognostic value of any measure of dysglycaemia as a continuous risk factor for future cardiovascular events such as myocardial infarction and heart failure. The relationship between dysglycaemia and cardiovascular outcomes was amplified in the DECODE study, including both FPG and 2-hPG. The results were very clear: FPG did not independently predict all-cause and cardiovascular mortality, but 2-hPG did.9 In people with T2DM based on FPG, mortality was increased only in those who also had high 2-hPG. Because the OGTT is the most sensitive measure of pre-diabetes and undiagnosed T2DM, and because the 2007 ESC guidelines specifically included IGT, the rest of this commentary focuses on the importance of keeping IGT as determined by the OGTT in diabetes and cardiovascular guidelines. In the EUROASPIRE IV and V surveys, the prevalence of IGT in coronary patients was not trivial, being 17% and 15% in all women and men, and 28% and 23% among those without previously known glucose perturbations.10
The implication of impaired glucose tolerance
The stated purpose of the 2007 ESC Guidelines was: ‘To improve the management of patients with overt diabetes, patients at risk of developing diabetes, as demonstrated by impaired glucose tolerance, and cardiovascular diseases in these patient populations’.1 The importance of screening for glucose perturbations was emphasized for patients with manifestations of atherosclerotic disease or at high risk for such complications. Although less was known about IGT at that time, those guidelines stated that ‘there is an increasing interest in identifying people with IGT, who might benefit from lifestyle or pharmacological intervention to reduce and delay the progression to diabetes’. That statement was supported by an overview of major diabetes trials by Tuomilehto and Lindström.11 Since then, several studies have revealed that newly detected IGT is almost as prognostically unfavourable as newly detected T2DM. One of the first reports was presented by Ritsinger et al.12 in 2015. In a 10-year-long follow-up of the Glucose Tolerance in Patients with Acute Myocardial Infarction (GAMI) trial, newly identified dysglycaemia, either in the form of IGT (n = 58) or as T2DM (n = 55), was an important predictor of cardiovascular events in patients with a previous myocardial infarction, with no significant difference between the two. Similar findings were presented by George et al.13 who followed 768 patients with myocardial infarction without previously known diabetes. Their glycaemic state was categorized by means of a pre-discharge OGTT, and they were followed during an average of 47 ± 9 months. Those with IGT had a significantly higher number of cardiovascular events during the follow-up although somewhat less that those with newly detected T2DM. Moreover, Chattopadhyay et al.14 demonstrated that an elevated 2-hPG in the IGT range is an independent predictor of adverse outcome after an acute coronary event (n = 1056) during a median time of 3.4 years of follow-up even after adjusting for the Global Registry of Acute Coronary Events (GRACE) risk score. In these three studies, Kaplan–Meier curves demonstrated that the higher event rate among patients with IGT appeared rather early, i.e. within a year. This underlines the importance to detect pre-diabetes early after the acute event to enable appropriate management without unnecessary delay. Finally, Laichuthai et al.15 combined studies on patients who had suffered an acute myocardial infarction in a meta-analysis, demonstrating an association between pre-diabetes and all-cause mortality, major adverse coronary events, and hospitalization for heart failure. Taken together, these findings highlight the importance of identifying previously undetected, as well as overt T2DM. Thus, looking backward, the inclusion of IGT in previous versions of the guidelines was insightful, and its preservation in the 2013 and 2019 versions understandable, while its sudden omission in the 2023 version seems hard to justify against the accumulating scientific evidence. The decision to omit pre-diabetes appears to be based on an analysis of data16 that was restricted to people without a known history of cardiovascular disease, in which most participants had only one measurement of dysglycaemia. However, the guidelines here neglected the previously cited large meta-analysis of people with pre-diabetes,8 and other data reporting that the 2-hPG predicts future mortality and cardiovascular events in people with previous cardiovascular disease when all glycaemic measures are accounted for in the same study.12–14,17–19 Indeed, when the 2-hPG level is available, it attenuates any cardiovascular risk associated with either FPG or HbA1c and remains the only independent cardiovascular risk predictor.9,17–21
Why is the oral glucose tolerance test downgraded?
The 2023 ESC Guidelines do not exclude the use of the OGTT, but only recommend its use where glycaemic status remains unclear following FPG and HbA1c measurements.4 A similar limitation was already present in the 2013 and 2019 versions of the guidelines, but these versions still advocated that attention should be paid to the detection of IGT.2,3 We believe that the omission of pre-diabetes as a risk factor means that important diagnostic and prognostic information will be missed. It is important to keep in mind that elevation of FPG and 2-hPG has different pathophysiologies: high FPG mainly indicates hepatic dysfunction in glucose regulation, while high 2-hPG is a postprandial glucose problem indicating decreased pancreatic insulin secretion and increased insulin resistance in peripheral tissues.
The reason given for reducing the use of the OGTT is said to be that ‘it is considered time-consuming and inconvenient, not the least since it requires that the patient is investigated in the fasting state’.4 This is hard to justify considering that the information provided may have important management implications both related to lifestyle recommendations and for the choice of pharmacological treatment during many years of life. It is possible to prevent the progression from IGT to T2DM, and this has proven successful in reducing mortality, cardiovascular events, and heart failure both by lifestyle modification and pharmacological agents targeting insulin resistance and other glucometabolic pathways, as exemplified by the Da Qing and Insulin Resistance Intervention after Stroke (IRIS) trials.22,23 Most recently the SELECT trial tested semaglutide vs. placebo in a randomized, event-driven superiority trial, on 17 604 overweight or obese patients with cardiovascular disease but without any history of diabetes. The HbA1c was >5.7% (>39 mmol/mol) in 66% of the patients, confirming that a large proportion of such patients must have had pre-diabetes at the start of the study even in the absence of an OGTT (a shortcoming of this well-conducted trial). After a mean follow-up of 39.8 ± 9.4 months, there was a 20% relative reduction of the primary cardiovascular endpoint, a composite of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke (hazard ratio 0.80; 95% confidence interval 0.72–0.90; P < .001). Thus, the importance for patients with pre-diabetes must be considered confirmed.24
Compared with many interventions and therapeutic options that, without hesitancy, are recommended by the latest ESC Guidelines for the category of patients taken into consideration, the omission of an inexpensive, uncomplicated, informative test with a duration of about 2.5 h as part of a comprehensive investigation is hard to justify.
In conclusion, in patients with acute coronary syndromes, several well-conducted investigations have shown that pre-diabetes, at least in the form of IGT, significantly increases the risk for future cardiovascular events. These appears rather early after the index event. Thus, it is important to identify IGT in the current patient population as soon as possible. An easily applied, informative test is available in the form of an OGTT. That this test takes somewhat more than 2 h and has to be performed in the fasting state should reasonably not be used as solid argument to abstain from the identification of two important risk factors, newly detected IGT and T2DM. To use HbA1c for this purpose does not provide similar information. To screen for IGT, and not only T2DM, makes sense. Glucose is a continuous risk factor with IGT almost as serious as T2DM. Detection of IGT provides an opportunity to manage the patients in question with both lifestyle-oriented and pharmacological tools of proven therapeutic value in affecting hard outcomes. Thus, the elimination of pre-diabetes from the 2023 guidelines represents an action of ignorance in our minds.
Declarations
Disclosure of Interest
L.R. reports research grants from the Swedish Heart Lung Foundation, Region Stockholm and E Persson’s Foundation, Amgen, Boehringer Ingelheim, and Novo Nordisk. He receives honoraria for consulting and lecturing from Bayer AG, Boehringer Ingelheim, and Novo Nordisk. H.C.G. reports research grants from Eli Lilly, Novo Nordisk, Hanmi, and Sanofi; honoraria for speaking from AstraZeneca, Eli Lilly, Novo Nordisk, DKSH, Zuellig, Sanofi, Jiangsu Hanson, and Carbon Brand; and consulting fees from Abbott, Bayer, Biolinq, Eli Lilly, Novo Nordisk, Sanofi, Kowa, Pfizer, and Hanmi. J.C. reports receiving grants (through institutions) and/or honoraria for consultancy or giving lectures from Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Celltrion, Eli Lilly, Hua Medicine, Powder Pharmaceuticals, Roche, Merck, MSD, Pfizer, Sanofi, Servier, Viatris, and Zuellig Pharma. F.C. reports research grants from Swedish Research Council, Swedish Heart and Lung Foundation, Swedish Diabetes Foundation, and King Gustav V and Queen Victoria Foundation and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Novo Nordisk, and Pfizer. K.K.R. reports unrestricted research grants to Imperial College London from Amgen, Daiichi Sankyo, Regeneron, Sanofi, and Ultragenix; and personal fees for SC, EC, or advisory board from Novartis, Esperion, Daiichi Sankyo, Abbott, Bayer, Eli Lilly, Silence Therapeutics, CSL Behring, New Amsterdam Pharma, Sanofi, Amgen, Novo Nordisk, BI, Scribe, Vaxxinity, CRISPR, AZ, Kowa, and Cargene; and honoraria for CME and non-CME from Novartis, Novo Nordisk, BI, AZ, Viatris, Daiichi Sankyo, Amgen, and Sanofi, and stock options from New Amsterdam Pharma and PEMI-31. S.V. reports research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc, and Sanofi. L.M. reports research grants from the Swedish Heart and Lung Foundation and Region Stockholm and consulting and speaker fees by Amgen, Amarin, Astra Zeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, and Sanofi, and received research grants from Amgen and Bayer AG. R.R.H. reports personal fees from Anji Pharmaceuticals, AstraZeneca, Novartis and Novo Nordisk. E.S. reports no conflicts of interest. S.V. reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc, and Sanofi. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. D.W. reports no conflicts of interest. J.T. reports ownership of stocks in Orion Pharma, Aktivolabs LTD, and Digostics LTD.
