Summaries of selected highlights of the 1 st International Congress on ‘Prediabetes’ and the Metabolic Syndrome, Berlin, Germany, April 13-16, 2005

Friday April 15

08.30-10.30 Plenary session: Pharmacological prevention of diabetes in high-risk populations supported by an unrestricted educational grant from AstraZeneca Knowler W, Karasik A, Buchanan T, DeFronzo R, Gerstein H, Holman R and Ramachandran A

The first part of the opening session for today’s meeting focused on the results of recent trials of diabetes prevention.

Lifestyle intervention vs pharmacological management (Summary of an oral presentation by Dr Knowler)

In his presentation, Dr Knowler described the Diabetes Prevention Program (DPP), which was initiated several years ago based on the fact that type 2 diabetes can be prevented or delayed by treating modifiable risk factors. These include obesity, physical inactivity, elevated fasting or 2 hour plasma glucose levels that are not at the diagnostic level for diabetes, insulin resistance and impaired insulin secretion.

The DPP was a US-based multicentre, randomised clinical trial involving patients with a high risk of type 2 diabetes, and having impaired glucose tolerance and impaired fasting glucose. Primary outcomes were development of diabetes as assessed by fasting plasma glucose every 6 months and an oral glucose tolerance test conducted annually. Patients received advice on diet and exercise, and were randomly assigned to receive treatment with placebo (n=1,082), metformin (n=1,073), troglitazone (n=387) or intensive lifestyle intervention (n=1,079). For the intensive lifestyle intervention, patients were instructed to carry out ≥ 150 minutes/week moderate physical activity, and lose ≥ 7% of their body weight. The incidence rate of diabetes was highest in the placebo group (12), followed by metformin (6.7), intensive lifestyle intervention (5.1), and lowest with Troglitazone (3.0) (Troglitazone vs placebo p<0.001). Intensive lifestyle intervention was associated with greatest weight loss whilst patients receiving Troglitazone had the greatest weight gain.

During 0.9 years of follow-up, diabetes incidence in the troglitazone group (3.0 cases per 100 person-years) was slightly lower than that with lifestyle intervention and significantly lower compared with placebo or metformin. However, the preventative effect of troglitazone was not maintained after discontinuation. Dr Knowler explained that troglitazone was discontinued on June 4 1998 following liver toxicity concerns, and these patients received group lifestyle classes that were not as intensive as the lifestyle intervention group.

The main results of the study were released in 2001 and reported no difference between fasting plasma glucose in those subjects receiving intensive lifestyle intervention or metformin, whilst the placebo group had a steady increase. The hazard rate reduction for development of diabetes was 31% in the metformin group and 58% in the lifestyle intervention group. After an average of 2.8 years follow-up, the incidence of diabetes was significantly lower in the lifestyle intervention group (4.8 cases per 100 person-years) compared with the metformin and placebo groups (7.8 and 11.0 cases per 100 person-years, respectively) [p<0.001]. In terms of the number of patients who would require treatment to prevent 1 case of diabetes in 3 years, this was 13.9 for metformin compared with 6.9 for the lifestyle intervention group.

Dr Knowler concluded that lifestyle and pharmacological interventions were effective in short-term studies but that intensive lifestyle intervention was more effective than metformin at preventing diabetes. At best, effective treatments lower the incidence rates of diabetes but do not reduce it to zero, and it is currently unclear when is the optimal time to start interventions. The long-term benefits of pharmacological treatment on cardiovascular disease or other complications remain unknown. In Dr Knowler’s opinion it may be best to intervene on early life risk factors for example, genetic or childhood factors although this would be difficult due to the long-term follow-up required for such studies.

Efficacy of acarbose in delaying the development of diabetes (Summary of an oral presentation by Dr Karasik)

Dr Karasik described the multicentre, international STOP NIDDM trial whose primary outcome was to evaluate the effect of acarbose treatment in preventing or delaying the development of impaired glucose tolerance (IGT) into type 2 diabetes. The main secondary outcome was to determine the effect of acarbose on cardiovascular events although this will be summarised during Dr Chiasson’s presentation in Saturday’s plenary session.

Patients with both IGT and IFG [fasting blood glucose >5.6 mM (100 mg/dl)] were randomised to receive either acarbose (up to 100 mg tid) or placebo. Patients were followed for ≥ 3 years, and this was followed by a wash-out period of 3 months. Of 1,429 patients initially randomised, 682 patients received acarbose and 686 patients received placebo. Thirty one percent of patients in the acarbose group and 19% of patients in the placebo group discontinued treatment, mainly during the first 6 months. The main reason for discontinuation in the acarbose group was related to the known gastrointestinal side effects of acarbose (flatulence and diarrhoea).

In terms of the incidence of diabetes, separation between the two groups was evident even after 1 year, and after an average of 3.3 years, 32% of patients receiving acarbose developed diabetes compared with 42% of those receiving placebo. Dr Karasik told the audience that this represented a significant reduction of 25% in the risk of diabetes with acarbose (p=0.0015 using Cox proportional hazard model), and this significance held even after multivariate analysis. There was an absolute risk reduction of 9.1% over 3.3 years suggesting that 11 patients would need to be treated to prevent one case of diabetes. Reversion of IGT to normal glucose tolerance was significantly increased in patients receiving acarbose (p<0.0001), whereas treatment with placebo was associated with increased conversion of IGT to diabetes.

A question that was raised in this presentation and those also included in the session relates to whether or not the onset of diabetes is being prevented or simply delayed? Results from the wash-out period, which was specifically designed to answer this question, showed that a larger proportion of patients who had received acarbose (6.9) developed diabetes compared with the placebo group (3.1). Dr Karasik remarked that the results from the STOP NIDDM trial support the notion that postprandial hyperglycaemia plays an important role in the progression of IGT to diabetes and that acarbose may be used to modify this process in high-risk individuals.

Prevention of diabetes with troglitazone or pioglitazone (Summary of an oral presentation by Dr Buchanan)

The session continued with Dr Buchanan’s presentation of the Troglitazone in Prevention of Diabetes (TRIPOD) and Pioglitazone in Prevention of Diabetes (PIPOD) studies, in which prevention of diabetes was investigated in Hispanic-American women with recent gestational diabetes. Dr Buchanan opened his presentation by describing the relationship between type 2 diabetes and ‘prediabetes’. From the USC GDM cohort study, ‘prediabetes’ can be defined as a long period of loss of β-cell function, which is associated with rising glucose levels. Dr Buchanan suggested that impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are not ‘prediabetes’ but are associated risk factors based on the finding that patients with normal glucose tolerance can have ‘prediabetes’.

Dr Buchanan described the TRIPOD study, which involved 266 women randomised to receive either troglitazone or placebo. There was a 55% relative risk reduction and 31% absolute risk reduction in diabetes incidence during a median of 3 months on troglitazone (400 mg/day), compared with placebo. A close association existed between reduction in insulin secretion during intravenous glucose tolerance tests at 3 months ( β-cell rest) and protection from diabetes. Persistent diabetes protection at 8 months post-drug testing suggesting that troglitazone had modified the natural history of progression towards type 2 diabetes. There was stable glucose and β-cell function for 4.5 years in women who did not develop diabetes on troglitazone.

Eighty-six women who completed the TRIPOD study participated in the open-label PIPOD trial. They received pioglitazone for 3 years, and this was followed by a 6-month wash-out period. Treatment was associated with a relatively low incidence of diabetes, there was stabilisation of falling β-cell function in women who were losing function in the placebo group of the TRIPOD study, and β-cell rest was associated with protection from diabetes.

Dr Buchanan finished his presentation by trying to incorporate the information he had presented into the context of pharmacologogical treatment for the prevention of diabetes. The population can be divided into subjects who are diabetic and require treatment, subjects with normal fasting glucose but a low risk of having ‘prediabetes’, and subjects with a high risk of developing ‘prediabetes’ who require aggressive diet and exercise intervention combined with monitoring of their glycaemic stability. In Dr Buchanan’s opinion, it is this latter group of patients who require pharmacological intervention.

Ongoing diabetes prevention trials

During the second part of the session, the speakers introduced the audience to a series of diabetes prevention trials that are still recruiting patients or are currently underway.

Can pioglitazone prevent or delay onset of type 2 diabetes in IGT patients? (Summary of an oral presentation by Dr DeFronzo)

Dr DeFronzo began by describing the ACT NOW trial, which is examining whether early treatment with pioglitazone (45 mg/day) can prevent or delay the onset of type 2 diabetes in patients with impaired glucose tolerance (IGT). In addition, ACT NOW will also measure improvement in glycaemic control, improvement in both micro- and macrovascular cardiovascular risk factors and indices of atherosclerosis, enhanced β-cell function, improved insulin sensitivity, and changes in body weight and composition.

ACT NOW is a 45-month prospective, double-blind, randomised, placebo-controlled clinical trial that aims to recruit 600 subjects with IGT and fasting plasma glucose (FPG) levels of 95 mg/dl. Individuals must also have at least one additional high-risk factor for type 2 diabetes, for example family history of diabetes or a component of the metabolic syndrome. To date, 306 patients have been enrolled, and it is estimated that recruitment will be complete by October this year. Patients receive treatment for 24 months, and during this time their fasting plasma glucose is assessed every 3 months. Their oral glucose tolerance is assessed every year and then at 45 and 51 months after treatment or if their fasting plasma glucose is ≥ 126 mg% at any visit. It is predicted that data will be available for presentation in 1.5–2 years time.

The DREAM trial (Summary of an oral presentation by Dr Gerstein)

Dr Gerstein discussed the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial. Dr Gerstein began by asking the question, why is prevention of diabetes important? Clinical trials have shown that if diabetes can be prevented, this may prevent the consequences associated with diabetes such as complications affecting the eye, kidney or renal systems, although it is still unclear if this applies to cardiovascular disease (CVD), which can develop even when subjects have glucose levels lower than the diabetes threshold. In addition, there is a possibility that normalising glucose homeostasis may reduce the incidence of CVD.

The DREAM trial aims to address two main points: does ramipril (15 mg/d) prevent the development of type 2 diabetes in non-diabetic individuals with either impaired glucose tolerance or impaired fasting glucose compared with placebo, and does rosiglitazone (8 mg/day) prevent the development of diabetes in the same population compared with placebo? Recruitment was initiated in July 2001 and completed in August 2003. Follow-up will last for 3–5 years, but it is estimated that the trial will be completed in 2006 with data available for discussion in 2007. The final sample size is 5,269 individuals, and a number of sub-studies are being carried out including an ultrasound study in 1200 individuals and an epidemiological study (EPIDREAM) that involves the 25,000 individuals initially screened for the DREAM trial.

Primary outcome is the development of diabetes or death from any cause in individuals who did not have diabetes. There are a number of secondary outcomes including changes in β-cell function and insulin resistance, as well as composite cardiorenal outcome. If patients develop diabetes, they will remain on their assigned study medication although other anti-diabetic drugs will be administered as required. There will also be a 3-month wash-out period at the end of the study to assess whether the risk of developing diabetes was prevented or masked.

Dr Gerstein concluded his presentation by re-iterating that the questions to be answered are does a drug that safely reduces the risk of CVD also reduce the risk of diabetes, does an insulin sensitiser that safely lowers glucose levels in diabetes also reduce the incidence of new cases of diabetes, does either drug safely reduce the risk of atherosclerosis, and finally does either drug affect the natural history of β-cell dysfunction?

Can treatment with nateglinide and/or valsartan prevent type 2 diabetes and CVD? (Summary of an oral presentation by Dr Holman)

In the following presentation, Dr Holman described the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, which Dr Holman stated is complimentary to the DREAM trial although the NAVIGATOR trial is larger and associated with different outcomes. The NAVIGATOR trial is investigating whether treatment with a prandial glucose regulator (nateglinide 60 mg) and/or an angiotensin 2 receptor blocker (valsartan 160 mg/day) can delay or prevent progression of impaired glucose tolerance (IGT) to type 2 diabetes. Based on previous studies it seems reasonable to test the hypothesis that an agent, which improves insulin secretion immediately after meals but not between meals and reduces post-prandial hyperglycaemia, may have an impact on cardiovascular disease (CVD).

All subjects must have IGT but one-third will have known CVD and be aged ≥ 50 years, whilst the remaining two-thirds will have at least one CVD risk factor and be aged ≥ 55 years. Subjects are randomly assigned to one of 4 treatment groups: nateglinide, valsartan, nateglinide and valsartan, or placebo, and a wash-out period is included at the end of the trial. Although this is a placebo-controlled trial, patients are given information on lifestyle modifications aimed at reducing weight and dietary fat, and increasing physical activity. During the initial screening of 43,509 subjects with the OGTT, 37.5% had NGT, 12.2% had isolated impaired fasting glucose, 28.3% had IGT and 22.0% had unrecognised diabetes.

Dr Holman told the audience that the final analysis of primary CVD events is expected to occur late in 2007, and it is anticipated that the results will be available in 2008. Dr Holman ended the presentation by saying that the NAVIGATOR trial is the only study powered to examine directly the potential for reducing the risk of CVD in addition to decreasing the risk of developing type 2 diabetes. There is an urgent need for a large-scale prevention programme to target those people who have been identified as being at high risk of CVD and diabetes.

Effect of LSM and/or metformin in Asian Indians (Summary of an oral presentation by Dr Ramachandran)

Dr Ramachandran gave the final presentation of the session. He explained that it was not possible to apply conventional diabetes risk factors to the Asian Indian population due to differences in body mass index, weight and age. In addition there are differences in anthropometric and biochemical features, which are determinants of diabetes, and Indians may be relatively non-obese but highly insulin resistant.

The feasibility and effectiveness of the primary prevention of type 2 diabetes using lifestyle modifications (LSM) and/or metformin in Asian Indians, has been tested in the Indian Diabetes Prevention Programme (IDPP). This is one of the first prevention programmes in a developing country. Subjects aged 35-55 years, with persistent impaired glucose tolerance (IGT) were randomised into 4 groups and received no intervention (control), LSM including dietary modification and increased physical activity, metformin alone or LSM plus metformin. All groups were assessed with the oral glucose tolerance test and a personal interview. Adherence to interventions was also assessed.

The conversion rates to diabetes at 3-year follow-up were 49.6% for the control group, 39.8% for metformin, 35% for LSM and 34.7% for LSM/metformin (with LSM and LSM/metformin reaching significance). The proportion remaining free from diabetes were 35.1% for the control group, 45.0% for metformin, 48.5% for LSM and 56.3% for LSM/metformin (with LSM and LSM/metformin reaching significance).

Dr Ramachandran summarised his presentation by stating that the conversion rate of IGT to diabetes was very high in the Indian population (49.6% over 3 years), conversion to diabetes was significantly reduced by LSM without weight reduction (29.5%), metformin alone without weight reduction reduced conversion to diabetes and this was significant when metformin was added to LSM although the addition of metformin did not significantly improve the outcome compared with LSM alone. The number of people who would be required to receive treatment in order to prevent diabetes in 1 person by LSM was 6.9, which was identical to that of the DPP. In contrast for metformin, this number was 10.2 which is lower than that reported by the DPP (13.9). In conclusion, primary prevention of diabetes is possible in subjects with IGT without significant weight reduction by LSM and addition of metformin.

Are we actually preventing or treating type 2 diabetes? (Summary of roundtable discussion)

The session ended with a roundtable discussion involving all speakers, and centred mainly around the question ‘do pharmacological interventions really prevent the development of diabetes or are they rather masking and treating the underlying factors? The general consensus of the panel was that the underlying mechanism was not as important as the fact that the incidence of diabetes was being reduced.

In addition, pharmacological treatments are treating risk and this is what was considered by the panel to be important. It was proposed that such treatments rather than masking diabetes do actually treat the early stages of diabetes. However, it is important to look at the effect of masking when investigating the effect of drugs.

11.00-12.30 Parallel session: Non-pharmacological prevention of diabetes in high-risk populations Tuomilehto J, Barrett-Connor E and Holman R

Finnish prevention study (Summary of an oral presentation by Dr Tuomilehto )

Dr Tuomilehto opened the session by discussing the Finnish Diabetes Prevention Study, which investigated if lifestyle guidance in people with impaired glucose tolerance (IGT) could prevent or delay the development of diabetes. The study enrolled 522 subjects aged 40–65 years with IGT. The five intervention goals of the study were weight reduction, reduction in total fat and saturated fat, an increase in dietary fibre and 30 minutes of physical activity per day.

Dr Tuomilehto continued his presentation by describing the primary outcomes of the study. Saturated and total fat were reduced and dietary fibre intake was increased in the intervention group compared with the control. In addition, physical activity patterns changed such that at the end of year 1, 26% of people in the intervention group were more active. In addition to the primary outcomes, the incidence of diabetes was significantly reduced by 58% in the intervention group compared with controls. The intervention effect was immediate, occurring as early as year 1 and by year 2 was statistically significant between the intervention and control groups.

Furthermore, in the intervention group, the risk of diabetes in people who were physically inactive at the start of the study, became similar, following lifestyle guidance, to those in the control group who were more active at the start of the study. In patients in the intervention group who were physically active to start with, the risk of diabetes was reduced drastically.

Dr Tuomilehto concluded his presentation by discussing whether type 2 diabetes is prevented or delayed by lifestyle interventions. The weight change was long-lasting as were lifestyle changes which were maintained after 6 years. In addition, after 10 years, the difference in reducing the risk of diabetes between the intervention group and controls was further increased. This indicates that permanent effects are being achieved.

Intensive lifestyle intervention vs metformin in prevention of metabolic syndrome (Summary of an oral presentation by Dr Barrett-Connor )

Following on from Dr Knowler’s presentation earlier in the day, Dr Barrett-Connor presented further results from the Diabetes Prevention Program (DPP) including the incidence of metabolic syndrome. The trial compared the impact of lifestyle interventions with metformin or placebo in US patients at high risk of type 2 diabetes.

Patients in the lifestyle intervention group lost more weight than those in the metformin group, even though over the 4-year period their weight started to return to baseline. The mean change in fasting plasma glucose (FPG) was the same in the lifestyle intervention group compared with the metformin group but post-prandial glucose were more effectively reduced by lifestyle interventions than metformin or placebo. Metformin and lifestyle interventions were equally effective in preventing diabetes in younger patients (23–44 years) but in the oldest patients, metformin was no better than placebo and only lifestyle interventions had an effect in preventing diabetes. Additionally, in patients with a lower BMI, lifestyle interventions were more effective than metformin or placebo in preventing diabetes, whereas in patients with high BMI, metformin and lifestyle interventions were equally effective.

She explained that individuals with impaired glucose tolerance (IGT) have a high prevalence of cardiovascular disease (CVD) risk factors, collectively referred to as the metabolic syndrome. In the DPP, prevalence of metabolic syndrome at baseline and the effect of lifestyle interventions, metformin or placebo on new metabolic syndrome incidence (using >3 of the following criteria: high fasting plasma glucose (FPG), elevated triglycerides, abdominal obesity, high blood pressure and low high-density lipoprotein-cholesterol [HDL-C]) were investigated.

Dr Barrett-Connor continued by highlighting that baseline prevalence of metabolic syndrome was comparable among the treatment groups (53%), although low HDL-C was more frequent in younger subjects (70% vs 41%) and high blood pressure was more frequent in older subjects (31% vs 63%). However, in 1,523 subjects without metabolic syndrome at baseline, new incidence of metabolic syndrome was significantly reduced by 41% (p<0.001) and 17% (p<0.04) in those receiving lifestyle interventions and metformin, respectively, compared with placebo. DPP interventions were most effective at significantly reducing the incidence of abdominal obesity [78%, lifestyle interventions; 50% metformin (both p<0.001) compared with placebo] and equally effective in reducing the incidence of high FPG (43%), but reduction of low HDL-C incidence was non-significant in both groups.

Dr Barrett-Connor concluded that although both lifestyle interventions and metformin reduced the risk of developing metabolic syndrome, lifestyle interventions was twice as effective as metformin.

Acarbose vs metformin in prevention of diabetes (Summary of an oral presentation by Dr Holman)

Dr Holman presented the results for the Early Diabetes Intervention Trial (EDIT), in which 631 UK subjects, thought to be at increased risk of diabetes, were randomised to acarbose 50 mg three times daily or placebo and metformin 500 mg three times daily or placebo for 6 years. At baseline, 17% of these subjects had 2-hour plasma glucose values of 11.1 mmol/L, 37% had impaired glucose tolerance (IGT), 21% had IFG and 46% had normal glucose tolerance.

Following 6 years of treatment, 31% of subjects had developed diabetes while 14% had discontinued treatment. Overall, the relative risk for developing diabetes was similar among treatment groups (1.04, acarbose; 0.99, metformin and 1.02, combination). However, in patients with IGT at baseline, relative risk was significantly reduced with acarbose (0.66, p=0.046) but not with metformin (1.09) or combination therapy (0.72). Since relatively few people took all the therapy for the whole study, the data were analysed for patients who actually received therapy. Again, the relative risk for developing diabetes was similar among treatment groups (0.80, acarbose; 0.91, metformin and 0.75, combination). However, in patients with IGT at baseline, relative risk was significantly reduced with acarbose (0.34, p<0.001) but not with metformin (1.29) or combination therapy (0.44). Age, BMI and fasting plasma glucose did not have significant effects on the relative risk for developing diabetes.

Dr Holman ended his presentation by summarising the results of the EDIT study that showed that there were no significant differences in glycaemic progression with acarbose or with metformin, or with a combination of both agents in subjects with fasting hyperglycaemia and risk factors for type 2 diabetes.

16.00-17.30 Parallel session: Epidemiology of CVD in ‘pre-diabetes’ and the metabolic syndrome Gerstein H, Heine R and Nesto R

Epidemiological evidence that dysglycaemia is a risk factor for CVD (Summary of an oral presentation by Dr Gerstein)

Dr Gerstein opened the session by presenting epidemiological evidence that a rise in glucose above normal predicts future cardiovascular (CV) events. In order to investigate the risk of CV events associated with glucose levels, a meta-analysis of prospective studies was performed, in which HbA1c was measured with CV risk as the outcome. For every 1% rise in HbA1c in people with diabetes, there is an 18% rise in the risk of CV events. Similarly for every 1% rise in HbA1c, there is a 28% increase in peripheral arterial disease in people with diabetes. In people without diabetes, as the fasting plasma glucose (FPG) level and 2-hour plasma glucose levels rises, so does the risk of CV events. Other studies have also demonstrated an association with an increase in HbA1c and increases in CV events.

He continued his presentation by discussing studies that demonstrated that dysglycaemia is common in people who have had a CV event. In one study in India, nearly two thirds of subjects (64%) who had had a myocardial infarction (MI) had impaired fasting glucose (IFG), IGT or diabetes compared with 29% of controls. In addition, the Euro Heart survey showed that in 923 hospitalised patients with CV disease, 58% had IFG, IGT or diabetes compared with 42% of controls. In the same study, more than half (51%) of 1000 out-patients had IFG, IGT or diabetes compared with controls. Dr Gerstein described several other studies which have shown that a rise in glucose levels above normal predicts CV events in people who have already had a CV event.

Dr Gerstein concluded his presentation by discussing whether glucose lowering reduces CV events. The evidence from present clinical trials is not conclusive and these studies are ongoing.

‘Pre-diabetes’ and associated risk of CVD (Summary of an oral presentation by Dr Heine)

Dr Heine discussed the results of the Hoorn study, which compared the prevalence of the metabolic syndrome in a population-based cohort in the Netherlands when different definitions of the metabolic syndrome were applied (WHO, ATP III, EGIR, ACE). The 10-year risk of fatal and non-fatal CVD was also assessed. The study population were aged between 50 and 75 years, with no history of diabetes or CVD at baseline (1989–1990) but the prevalence of the metabolic syndrome at this time ranged from 17% to 32% according to the various definitions.

The ATP III definition for the metabolic syndrome was associated with a two-fold increase in age-adjusted risk of fatal CVD in men, and non-fatal CVD in women, whereas the other definitions were associated with slightly lower hazard ratios. The audience also heard that although the prevalence of hyperinsulinaemia was higher in subjects with multiple risk factors, higher risk was not more strongly associated with definitions including hyperinsulinaemia as a prerequisite for the metabolic syndrome. As patients have an increasing number of components of the metabolic syndrome, they have a step-wise increase in risk of CVD.

Dr Heine concluded his presentation by reminding the audience that, however defined, the metabolic syndrome carries about a two-fold increase in the risk of CVD in a European population but risk can be assessed more accurately by using a sum score of prevailing risk factors.

Metabolic syndrome and associated risk of CVD (Summary of an oral presentation by Dr Nesto)

In the final presentation of this session, Dr Nesto discussed the risk of cardiovascular disease (CVD) in association with metabolic syndrome. Dr Nesto asked what are the fundamental issues regarding the impact of insulin resistance on coronary heart disease (CHD)? There is a greater risk of acute coronary syndrome (ACS), an increased likelihood of developing ACS at a young age, and a poorer prognosis following any CHD event. The hypothesis underlying the higher risk for acute myocardial infarction in insulin resistance involves more extensive and progressive coronary artery disease (CAD).

In relation to the metabolic syndrome, low-high density lipoprotein-cholesterol is prominent in a large number of individuals, and this can be regarded as one of the main driving forces of cardiovascular disease (CVD). As a single entity, the metabolic syndrome more strongly predicts CHD, CVD and mortality than its individual components although the cut-off levels used for these components are not always clear. In terms of the hazard ratio for CHD, the greatest risk occurs for patients with both diabetes and CVD (11.3), whereas subjects with CVD or the metabolic syndrome have a risk of 6.8 and 5.0, respectively.

Dr Nesto continued by presenting data from a number of studies to show that there is an increased risk of CVD prior to the diagnosis of diabetes, and that CVD mortality in middle-aged men is doubled in the presence of the metabolic syndrome. As the number of risk factors associated with the metabolic syndrome increases, there is a greater risk of CHD death, non-fatal myocardial infarction and onset of diabetes.

In terms of hypertension, metabolic syndrome amplifies the cardiovascular risk independent of the traditional risk factors. In the presence of the metabolic syndrome, there is increased target organ damage in untreated hypertensive patients resulting in greater risk of ventricle damage. This indicates that hypertension is different in patients with the metabolic syndrome, and it has also been shown that hypertension is a more powerful CV risk factor in the setting of insulin resistance.

Insulin resistance increases the risk of plaque disruption and thrombosis. The metabolic syndrome and C-reactive protein (CRP) can predict the incidence of cardiovascular events, and CRP within the metabolic syndrome adds prognostic information to the ATP-III definition of the metabolic syndrome. When the clustering of macrophages in diabetic and non-diabetic atheromas is compared, the diabetic atheroma is rich in macrophages whereas the non-diabetic atheroma is poor. Atherosclerosis in youth is linked to obesity and also to early insulin resistance.

Dr Nesto concluded his presentation by trying to use his presentation to answer, which patients with the metabolic syndrome have a high risk of CVD? In relation to background components, this includes an early age of onset, female gender, a strong family history of premature CVD or a first-degree relative with type 2 diabetes, the presence of other inflammatory disorders, and evidence of vascular disease on examination or imaging. In relation to components of the metabolic syndrome, these include being very obese, having a fasting glucose >100 mg/dL, and microalbuminuria and a C-reactive protein of >3.0.

Disclaimer

This report is provided compliments of MSD on behalf of the organisers of the 1 st International Congress on ‘Prediabetes’ and the Metabolic Syndrome. Before prescribing any of the medicines discussed in these presentations please consult the local manufacturers’ prescribing information for full details. These views expressed herein are not necessarily those of Merck & Co., Inc., or its related affiliates.

Copyright © 2005 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.