1st International Congress on "Prediabetes" and the Metabolic Syndrome - Epidemiology, Management and Prevention of Diabetes and Cardiovascular Disease: Berlin, Germany, April 13-16, 2005

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

Saturday April 16

08.30-10.30 Plenary session: Prevention of CVD in ‘pre-diabetes’ – primary and secondary. Supported by an unrestricted educational grant from Sanofi-Aventis Chiasson J, Gerstein H and Yusuf S

Reduction in CV risk with acarbose (Summary of an oral presentation by Dr Chiasson )

Dr Chiasson opened today’s meeting by presenting cardiovascular results from the STOP-NIDDM trial. Evidence exists to indicate that post-prandial hyperglycaemia is a risk factor for diabetes and cardiovascular disease (CVD), and that impaired glucose tolerance (IGT) can be characterised by post-prandial hyperglycaemia. A number of studies have shown that there is a linear relationship between 2-hour post 75g glucose levels and progression to diabetes in subjects with IGT. This was also found for CVD, and was the main rationale for the STOP-NIDDM trial.

The main primary objective of the STOP-NIDDM trial was to evaluate the effect of acarbose treatment on the conversion rate of IGT to type 2 diabetes. Dr Chiasson summarised the main baseline demographic data: equal gender balance; recruitment of mainly Caucasian subjects; obesity and central obesity; >75% had the metabolic syndrome according to the new definition. Acarbose reduced the incidence of diabetes in subjects with IGT by 36%, and the relative risk of CVD by 49%. In a sub-study, acarbose reduced progression of intima media thickness (IMT) of the common carotid arteries by approximately 50% (p=0.027). Furthermore, in subjects with type 2 diabetes treatment with acarbose significantly reduced the incidence of any cardiovascular event (6.09 for acarbose vs 9.44 for placebo; p=0.0061).

Dr Chiasson concluded that in subjects with IGT or type 2 diabetes, decreasing post-prandial hyperglycaemia with acarbose was associated with a significant reduction in the risk of CVD. These observations are compatible with the concept of postprandial hyperglycaemia as a risk factor for diabetes and CVD. STOP-NIDDM is the first prospective intervention trial in support of this concept.

The ORIGIN study (Summary of an oral presentation by Dr Gerstein )

Dr Gerstein continued this session by discussing the ORIGIN trial (Outcome Reduction with an Initial Glargine INtervention). This is a large international, multicentre trial that involves glargine insulin and omega 3 fatty acids, and there are a number of premises upon which this trial is based. Diabetes, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) are common cardiovascular (CV) risk factors. Insulin is a very important hormone that is relatively or absolutely deficient in subjects with diabetes, IGT or IFG, and if increasing insulin levels can restore physiological levels of glucose levels, it may be possible to reduce CV events. In addition, insulin is safe, well-tolerated and easily titrated with no contraindications. It is also the only metabolic therapy that offers the chance of returning glucose levels to normal, and is the most frequent intervention strategy in outcome studies for type 1 and 2 diabetes. Newer insulin preparations such as glargine offer easier and more predictable ways of administration, which is in contrast to other insulin preparations that have daily peaks or day-to-day variation. Omega 3 fatty acids inhibit platelet aggregation, have anti-inflammatory properties, and may be associated with a decreased risk of coronary heart disease.

The ORIGIN study addresses two main questions. In high risk subjects with IGT, IFG or early diabetes, does insulin replacement therapy that targets fasting normoglycaemia, reduce the risk of CV events more than standard approaches to dysglycaemia? In this high risk population, do omega 3 fatty acid supplements reduce the risk of CV events? Subjects were recruited to the trial if they were greater than or equal to 50 years of age and had IGT, IFG or newly diagnosed type 2 diabetes. Subjects were still eligible if they had mild established type 2 diabetes although they must exhibit good glycaemic control following at least 10 weeks of treatment with a stable dose of one oral agent. Subjects must also have a high risk of CV events. Individuals are randomised to four groups: glargine and the fatty acid supplement omacor; glargine and placebo; omacor; placebo. Recruitment began in August 2003, and there will be a 3 - 5 year follow-up period.

Dr Gerstein concluded by saying that if the glargine arm of the ORIGIN trial is positive, this implicates an abnormal glucose metabolic state as a causal factor for CVD. If the omega 3 arm of the ORIGIN trial is positive, this implicates dietary composition as a causal factor for CVD.

Blockade of the rennin-angiotensin system in the prevention of diabetes (Summary of an oral presentation by Dr Yusuf )

Dr Yusuf reminded the audience that recent evidence from trials involving either angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBS), indicated that blockade of the rennin-angiotensin system (RAS) was likely to prevent diabetes. Such trials included the Heart Outcomes Prevention Evaluation (HOPE), Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM), and Losartan Intervention For Endpoint (LIFE) studies.

Dr Yusuf then introduced the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trials, both of which are further exploring RAS in the development of diabetes. The primary outcomes of ONTARGET are to evaluate if telmisartan and ramipril are more effective in reducing death from cardiovascular events such as myocardial infarction and stroke compared with ramipril alone, and to determine if telmisartan is as effective as ramipril. Secondary outcomes involve comparing treatments with respect to newly diagnosed coronary heart failure or diabetes, revascularisation procedures, and microvascular complications. The primary outcome of the TRANSCEND trial was a modified version of the ONTARGET primary outcome to investigate if telmisartan is more effective in reducing death from cardiovascular events compared with placebo. Secondary outcomes were similar to those of ONTARGET. Results from the ONTARGET and TRANSCEND programmes will be available in late 2007 or early 2008.

During the next part of Dr Yusuf’s presentation, he asked what are the putative mechanisms by which ACE inhibitors and ARBS reduce diabetes. These inhibitors increase the lipid storage capacity of the liver and muscle as well as increasing blood flow to the pancreas and skeletal muscle. In addition they enhance insulin sensitivity by increasing levels of both adiponectin and potassium, and increasing phosphorylation of the insulin receptor.

As described by Dr Gerstein during Friday’s plenary session, 25,000 people were screened to assess their eligibility for inclusion in the DREAM trial. Dr Yusuf explained that the epidemiological data accumulated would be used in the EPIDREAM study to investigate the metabolic syndrome. It is also hoped that a genetic analysis can be carried out using the samples collected during screening.

Dr Yusuf concluded his presentation by summarising that retrospective studies have shown the ability of ACE inhibitors and ARBs to reduce the incidence of diabetes, and that ACE inhibitors, and to some extent ARBs, decrease the risk of major vascular events in patients with diabetes who are at high risk of CV events. Dr Yusuf also highlighted the growing need for prospective studies, and that several ongoing studies will explore these issues further in patients with IGT.

11.00-12.15 Parallel session: Dysglycaemia and coronary artery disease Rydén L

The Diabetes Heart Survey (Summary of an oral presentation by Dr Rydén)

Dr Rydén described the Euro Heart Survey, which aimed to study the prevalence of abnormal glucose regulation in patients with coronary artery disease (CAD). The survey was performed in 110 centres in 25 countries and recruited patients referred to a cardiologist due to CAD. Consecutive patients aged 18 years and older with CAD, with and without diabetes, admitted to hospital or outpatient setting were screened. Patient data were collected via a web-based case report form.

Out of the 4961 patients recruited to the survey, 2107 were acute hospital admissions and 2854 were consulted on an elective basis. Known diabetes was more common than seen previously at 30.7% and was relatively evenly distributed over the centres. An oral glucose tolerance test (OGTT) was performed on the 1920 patients without known diabetes, of whom 923 were in the acute group and 997 were in the elective group. Patients without previously known diabetes were classified according to their glucometabolic state using WHO criteria. In the acute group, the proportion of patients who had normal glucose tolerance was 42%, 36% had impaired glucose regulation and 22% newly detected diabetes. In the elective group, 49% had normal glucose tolerance, 37% had impaired glucose regulation and 14% had newly detected diabetes.

Dr Rydén concluded that the survey demonstrates that normal glucose regulation is less common than abnormal glucose regulation in patients with CAD. OGTT easily discloses the glucometabolic state and should be included in routine evaluation of the total cardiovascular risk in patients with CAD. The knowledge of abnormal glucose regulation among these patients should influence their management because it has serious prognostic implications.

11.00-12.15 Parallel session: The coronary patient with dysglycaemia
Malmberg K

DIGAMI and beyond (Summary of an oral presentation by Dr Malmberg)

Dr Malmberg opened the presentation by describing how the long-term prognosis of diabetic patients experiencing an acute myocardial infarction (MI) was poorer compared to patients without diabetes mellitus. This poorer prognosis may be closely associated with glucose control. In diabetic patients with acute coronary syndrome, myocardial pump failure and a new event most commonly cause mortality. These events may occur due to diabetic patients having a more vulnerable non-infarcted myocardium following the negative impact on the vascular wall of a deranged myocardial metabolism and long-term glucose elevation.

The Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial was discussed during the presentation. This trial investigated if rapid normalisation of the deranged metabolic state by insulin-glucose infusion and continuous insulin-based glucose control during acute coronary syndrome was potentially beneficial both for development of pump failure and future development of vascular events. Overall, the intensive approach improved long-term mortality (3.4 years) by 28% (absolute reduction 11%), with a mortality reduction of 50% (absolute reduction 15%) in the pre-stratified group of patients without prior insulin treatment. Reductions in HbA1c were seen in the whole group and also in the group without prior insulin treatment.

Dr Malmberg continued his presentation by describing DIGAMI 2. The goal was to reduce blood glucose to 7-10 mm/l and fasting blood glucose (FBG) to 5-7 mmol/l and <10 mmol/l post-prandial. Three treatment strategies were compared: group 1 received acute insulin-glucose infusion followed by insulin based long-term glucose control; group 2 received insulin-glucose infusion followed by standard glucose control; group 3 received routine metabolic management according to local practice. No significant differences in either HbA1c or FBG levels (around 6.8%) were observed between the groups at the end of follow-up. In addition, the target FBG of patients in group 1 did not reach 5-7 mmol/l. There was no significant difference between the primary endpoint of mortality of groups 1 and 2, and group 3 showed a non-significant tendency to lower mortality. There were no significant differences in a composite endpoint of death, stroke and reinfarction. Epidemiological analysis confirmed that elevated glucose levels strongly predicted long-term mortality.

Dr Malmberg concluded that the results of DIGAMI 2 did not support the primary hypothesis that acute and long-term insulin treatment is superior to acute treatment only. This can be accomplished by alternative treatment to insulin provided the patient has efficient glucose control.

13.30-15.30 Plenary session and closing ceremony: Future directions and conclusions Yusuf S, Alberti G, Bennett P and Lefebvre P

Professor Segal opened this presentation by saying that until now the Congress has concentrated on past events. The aim of this session was to move into the future.

Dysglycaemia and CVD (Summary of an oral presentation by Dr Yusuf)

Dr Yusuf summarised the evidence for a link between dysglycaemia and the risk of cardiovascular disease (CVD), and the conventional viewpoint that reducing glucose levels should be associated with a corresponding decrease in CVD. However, there is currently no conclusive proof that this is the case. An alternative viewpoint is that increased glucose levels are an expression of underlying metabolic abnormalities, and it may be some aspects of these that are causally related to CVD.

Dr Yusuf then described what information is required to resolve whether elevated glucose levels are causally related to CVD. Surprisingly, experimental data from animal models have indicated that lowering of glucose levels is only associated with a modest decrease in atherosclerosis. Human trials are required to demonstrate that lowering glucose can reduce CVD, and different strategies should be investigated since each may have a different by-product effect. A number of trials including UKPDS, VACSDM, DIGAMI, UGDP, ACCORD, PROACTIVE, NAVIGATOR and ADVANCE, are currently underway to investigate the effect of glucose lowering on CVD, and more data should become available during the next 5 years.

Overwhelming evidence suggests that individuals with diabetes have a two-fold increase in the risk of suffering CV events. Dr Yusuf believes that even without altering glucose levels, the incidence of CVD and macrovascular disease could be reduced by up to 90% simply by altering certain risk factors, for example controlling blood pressure and treating patients with statins. Dr Yusuf presented evidence to show that the waist-hip ratio offers a better way of assessing the attributable risk to acute myocardial infarction than other markers including BMI. This was true for both men and women, and in every population studied worldwide.

Dr Yusuf then presented his explanations for the observed increase in CVD and diabetes by describing what factors have led to obesity, dyslipidaemia, dysglycaemia, and high blood pressure. A decrease in childhood infectious diseases has meant a greater number of middle-aged and older people. There is also increased tobacco use. Perhaps most importantly in Dr Yusuf’s opinion, there has been poor adaptation of humans to urbanisation, which has resulted in decreased physical activity during every day life, increased energy and fat consumption, and increased psychosocial stress. Dr Yusuf then presented data from 5000 Indians enrolled in the PURE study, divided into those living in either rural or urban settings. Those living in an urban area had greater fat intake, took less physical activity, had a higher number of motorised two-wheeled vehicles and televisions, and had a greater BMI compared with the rural population. Perhaps the most striking feature was the prevalence of diabetes, which was 19.3 in the urban population and 1.8 in the rural population.

To conclude his presentation, Dr Yusuf suggested that glucose elevation might be a causal risk factor for CVD although additional evidence is required to answer this question. In addition, physicians should be able to reduce the risk of CVD in patients with diabetes without having to lowering glucose levels. Dr Yusuf believes that a fundamental approach to preventing obesity, diabetes and CVD falls with all members of society and should include altering the environment people live in to encourage physical activity by better planning of transportation and urban dwellings, and introducing food policies to reduce both calorie and fat intake.

Are we ready to treat the metabolic syndrome? (Summary of an oral presentation by Professor Alberti)

Professor Alberti explained that in order to answer the question ‘Are we ready to treat the metabolic syndrome?’ it is important to clarify the purpose of treatment, which is to prevent macrovascular disease and also to prevent diabetes. In order to treat the metabolic syndrome, it is helpful to know what the metabolic syndrome is, and also what causes it. A working definition of the metabolic syndrome is close, but the aetiology of the metabolic syndrome is not known. There is a strong association between the metabolic syndrome and insulin resistance, although the causality is not known. Other factors such as endothelial dysfunction and cell membrane defects have also been suggested as having an aetiological role.

Professor Alberti commented that there is no evidence that treating insulin resistance per se eliminates the metabolic syndrome, and any treatment should prevent cardiovascular disease and diabetes as well as dealing with the metabolic syndrome. Current knowledge suggests that individual components of the syndrome such as central obesity, dyslipidaemia, dysglycaemia and hypertension should be treated and drugs like metformin and the glitazones should be used to raise insulin sensitivity.

He suggested that lifestyle management is the ‘magic bullet’ for treating the metabolic syndrome. With good lifestyle management, such as diet and physical activity, 90% of the problem would be eliminated. In terms of pharmacological management of the metabolic syndrome, there is no single agent and so treatment should be a systematic treatment for the components of the metabolic syndrome. In conclusion, Professor Alberti felt that we do not have a specific therapy to treat the metabolic syndrome but we are ready to treat individual components of the syndrome.

What role do governments have in preventing diabetes and CVD? (Summary of an oral presentation by Dr Bennett)

Dr Bennett opened his presentation by explaining that, although the extent and magnitude of the present and future burden of diabetes and related diseases is now well recognised by the medical community, the fundamental problem facing society is the prevention of these diseases.

The most important risk factors for type 2 diabetes are unequivocally obesity and physical inactivity. In particular, behavioural changes over the last 50 years have resulted in the emergence of obesity as a major public health problem. In Dr Bennett’s opinion, sound public health policies are needed at all levels of government to prevent worsening of the obesity epidemic. He described a variety of potential policies that could be implemented to address the problem, ranging from improvements in public education and school curricula about nutrition, better eating habits and the benefits of increased physical activity, to actions such as the redesign of cities and transportation systems to encourage safe walking and appropriate regulation of the food and advertising industries. Other options include subsidisation of healthy foods and taxation of harmful foods.

Dr Bennett stressed that this public heath concern is more challenging even than smoking prevention; government policies and actions over the last 40 years have been effective in reducing the frequency of smoking in developed countries. He warned that government actions to prevent obesity, and consequently diabetes and cardiovascular disease, would require intense, concerted efforts over many years.

Where do we go from here? (Summary of an oral presentation by Dr Lefebvre)

Dr Lefebvre opened his presentation by reminding the audience about the current prevalence of diabetes: 95 million cases of known diabetes, 95 million cases of unknown diabetes and 300 million cases of impaired glucose tolerance. Both the International Diabetes Federation (IDF) and the World Health Organisation (WHO) have projected the prevalence of diabetes in the future. The IDF projections are that there will be 324 million people with diabetes in 2025 and similarly, the WHO has projected that there will be 366 million people with diabetes by 2030.

As a major component of, and a major contributor to, major non-communicable diseases, diabetes is a threat to economic development. But this fact is not sufficiently recognised by organisations such as the World Bank, and the WHO. In order to change this, the IDF has reacted by including diabetes prevention in its mission statement, monitoring the prevalence of diabetes with the World Diabetes Atlas (www.eatlas.idf.org) and acting in partnership with the WHO in a programme called Diabetes Action Now. This programme aims to raise awareness and promote solutions for the prevention and control of diabetes. The programme has several components including raising awareness, supporting new studies to acquire knowledge to support awareness raising activities/economic impact, producing technical reports such as on the prevention of diabetes and its complications which will be available soon, and guidance for national healthcare policy makers on effective interventions. Already results from the media campaign are being seen, with articles in major newspapers reporting the increasing prevalence of diabetes.

Dr Lefebvre concluded by saying that the world has changed both in positive and negative ways. It is important to defeat the negative changes, such as diseases including cardiovascular disease, diabetes and metabolic syndrome and this 1 st International Congress on ‘Prediabetes’ and the Metabolic Syndrome has come at the right time.

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.