Slide 1

Thank you Denis for your kind introduction and I should say like everybody else I’m very happy to be here in this beautiful city. So my task is to give a presentation on the definition and epidemiology of the metabolic syndrome.

Slide 2

A very brief history. It was a Swedish doctor actually that is considered to be the first to point out that there are clusters of metabolic defects which may have an impact on cardiovascular disease. That was in the 20s. Then he grouped together hypertension, hyperglycemia and hyperuricemia. Then in the 40s Doctor Vague from France pointed out the association between the male type of obesity, the upper body obesity with cardiovascular risk as opposed to the more female type of obesity.

Slide 3

But the discussion about the metabolic syndrome came to a front in the late 80s when Reaven discussed the importance of insulin resistance for cardiovascular disease. He defined something which came to be called Syndrome X which comprised insulin resistance which then led to hyperinsulinemia, glucose intolerance, increased concentrations of triglycerides and low concentrations of HDL-cholesterol and hypertension.

Slide 4

The discussion about the metabolic syndrome has then gone on and has been more intense during the last, I would say 5, 6, 7 years. One of the main proponents of the use of a term called metabolic syndrome is Grundy from the United States. He has proposed the pathogenesis of the metabolic syndrome like this on this slide her with two main components; excess body fat and also insulin signalling defects. So the excess body fat is some sort of a prerequisite according to his idea and then other factors make the patient metabolic susceptible to the syndrome. Such factors then include adipose tissue disorders, abnormal fat metabolism, physical inactivity, aging, genetic variation and different factors which maybe toxic. For example, in renal failure patients, of course, there are a lot of uremic toxic factors that could influence.
In later presentations during these symposia we will hear about obesity and renal disease and also about insulin and insulin resistance and I will not go into that now.

Slide 5

So, I will discuss the definition of this syndrome and unfortunately, there is not one definition but fairly many. There is one definition defined by the WHO from the late 90s and according to this definition the patient to get the label of metabolic syndrome should have some sort of indication of insulin resistance and that could be obvious by impaired glucose intolerance or impaired fasting glucose or even an overt type 2 diabetes or a decreased insulin-sensitivity measured by any reliable method. In addition 2 of either central obesity, high lipids, hypertension, glucose or others here including microalbuminuria. Then perhaps the most commonly used definition is the one from ATP, adult treatment program I think it is number III and there is no basal requirement for insulin resistance, so to get the label of metabolic syndrome there you have to have 3 of the following; you have a waist circumference for males more than 102cm and for women a little less, high triglycerides and hypercholesterolemia or low HDL-concentration. Blood pressure about 130/85mmHg and fasting plasma glucose about 6.1 mmol/l. Then there is a stricter or more defined by the International Diabetic Federation where you have increased waist circumference plus any 2 of hypertriglyceridemia or low HDL-cholesterol or high a systolic blood pressure or a high diastolic blood pressure or fasting blood glucose above 5.6.
At the bottom you see there is an EGIR that is another definition the European Group of the Study in Insulin Resistance.

Slide 6

So, reading all those definitions it’s not unexpected that you can read in an article on the metabolic syndrome in the Lancet a couple of years ago that a metabolic syndrome is the master of disguise since it can present in various ways according to the different components that constitute the syndrome. What this gets me to think of is Humpty Dumpty. If you remember Humpty Dumpty from ‘Through the looking glass’ and that’s not because Humpty Dumpty looks like having the metabolic syndrome, it’s because the conversation he’s having with Alice. Humpty Dumpty says ‘When I use a word, it means just what I choose it to mean, neither more nor less’. And Alice questions this and says, ‘The question is, if you can make words mean so many different things’. Humpty Dumpty then replies, ‘The question is, which is to be the master, that’s all’. I would say unfortunately when it comes to the metabolic syndrome there is no master definition. We have all these definitions.

Slide 7

Anyway perhaps the most commonly used definition is the ATPIII definition and this slide shows the prevalence of metabolic syndrome in population studies in various parts of Europe and the World using this definition and you see here countries and you see the age ranges. Most commonly the middle-aged population is something between 20-30% and here you see the United States have a much higher prevalence of the metabolic syndrome.

Slide 8

So, it’s called the metabolic syndrome, it’s also called Syndrome X or the insulin resistance syndrome and it’s mostly used now to define a clustering of abnormalities with increased risk which carry an increased risk for the development of type 2 diabetes or cardiovascular disease.

Slide 9

In a value metanalysis it seems that patients defined as having metabolic syndrome have an increased risk for cardiovascular disease and here is 20 something studies and the authors of this metanalysis have taken all definitions into consideration. So irrespective of the definitions patients with the metabolic syndrome seem to have an increased risk for cardiovascular morbidity and the observation time varies from a few years to up to 10 years or something like that.

Slide 10

Here you see they have defined specific risk cardiovascular events in total and then cardiovascular death and so on. They have also made analyses where they have multiple correlations which lie behind this. They have included components in the definitions which means that when they come out significant, it means that syndrome gives more information than the individual components.

Slide 11

There is a problem though that in studies where different definitions of the metabolic syndrome have been compared, for example, in this study from Europe about 10.000 patients without diabetes mellitus included in DECODE cohorts, it’s a collaboration of population studies, they found that men, they compared 4 different definitions and by any definition 44% of the men were defined as having metabolic syndrome but only about 15% of them were defined as having metabolic syndrome with all definitions. For women it’s about the same. These patients were followed up for a maximum of 7-16 years depending on what cohort they belonged to. In men the presence of the metabolic syndrome by all definitions increased cardiovascular mortality significantly but in women the metabolic syndrome only defined according to the WHO definition remained significant after multivariate adjustment.

Slide 12

A little of the same results was received in a study in Sweden where about 5.000 people were defined according to 3 different definitions. The prevalence of the metabolic syndrome at baseline by any definition was 31.3% and by all definitions just 10 or 11%. These subjects were then followed up for 11 years and the metabolic syndrome based on any of these 3 definitions was associated with significantly increased risk for cardiovascular events. The hazard ratio was 1.59, 1.11 and 1.35 respectively by the 3 definitions. But it is of interest and importance to note that single factors such as smoking had an equal predictive value as the metabolic syndrome.

Slide 13

Another problem with the definitions of the metabolic syndrome has been commented on by Bakker et al, one of the following speakers. They looked at the Groningen cohort from the PREVEND study many thousands of patients and they then made a ROC curve analysis using the metabolic syndrome according to the definitions and according to the definition you have high blood pressure yes or no. You have high triglycerides yes or no. But all these values are continuous and you lose a lot of information when you don’t use the continuous values. You see here that compared with the dichotomised definitions this dotted line, if you take the continuous values, you get a much better curve. What’s really remarkable is that when you just look at the age, it gives the best prediction of all.

Slide 14

So what are the associations between metabolic syndrome and chronic kidney disease then?

Slide 15

There are not that many studies but there is a Japanese study looking at about 7.000 men. These were paying patients undergoing metabolic screening, so that might be some sort of, I don’t know if it is a positive or negative selection. Patients who are keen enough to pay to be investigated. Anyway the mean age was 50 years and the prevalence of the metabolic syndrome again according to this ATP definition was 12.4%.
The prevalence of CKD defined as an estimated GFR below 60 ml/min/year or dipstick proteinuria more than 1% plus or more than that, was 13.7%. The odds ratio for CKD was increased in patients with the metabolic syndrome with an odds ratio of 1.57. But it’s interesting to see that what was really different between patients with metabolic syndrome and without metabolic syndrome was the prevalence of proteinuria while the estimated GFR did not differ between the 2 groups. It’s also interesting to see how the patients with CKD also were very much influenced by age and sex. Also about the number of metabolic syndrome risk factors included in the definition. So the more risk factors you have, the higher the risk is.

Slide 16

There is a fairly similar American study from the NHANES population study about 6.000 US adults and the prevalence in this population was 24.7% metabolic syndrome and you see here is the distribution patients having 0, 1, 2, 3 and so on risk factors but overall patients defined as having metabolic syndrome was 24.7%. Patients with a metabolic syndrome had an increased risk of CKD with an odds ratio of 2.6 and also of microalbuminuria with an odds ratio of 1.89. You see here that the prevalence both for the CKD and microalbuminuria increased as the number of metabolic risk factors increased.

Slide 17

So this is the relation between the presence of metabolic syndrome and the prevalence of CKD. So the natural question is then is the metabolic syndrome a risk factor for the development of CKD?

Slide 18

There are a few studies. This is a study comprising about 10.000 US adults, middle-aged. 20% black and in this population at baseline 21% of the patients or subjects were defined as having metabolic syndrome. Of these 7% developed CKD after 9 years of follow up. Patients with the metabolic syndrome, as compared with patients without the metabolic syndrome had an increased risk with an odds ratio of 1.43. But what’s important to note is that it’s only hypertension of the risk factors that really carries a clear increase in risk when adjusted for age, gender, and race.

Slide 19

This is a Japanese study also comprising several thousands of patients. The prevalence of the metabolic syndrome at baseline was 13.8%. 5.7% in this cohort developed CKD or proteinuria after 5 years of follow up. Also the metabolic syndrome carried an increased risk with an odds ratio of 1.86. But again, it’s the systolic blood pressure that impresses among the risk factors. Obesity is also significant but the other risk factors are not.

Slide 20

This is a study from Tehran in Iran. They followed 4.600 patients and at baseline the prevalence of metabolic syndrome was 21, 22%. During a 3-year follow up period 2.4% of the patients had progressed to CKD with a GFR less than 60 ml/min. Metabolic patients 3.4%, those without metabolic syndrome 2%. So there was an increased risk with an odds ratio of 1.8.
Again, it’s hypotension that is the risk factor. Here it’s interesting to see that abdominal obesity seemed to be carrying a less risk for CKD.

Slide 21

So what is the association of metabolic syndrome and morbidity with advanced CKD?

Slide 22

Well, there aren’t many studies and the studies that are around have often used these definitions with several modifications. Anyway these studies are also much smaller naturally. There is a cross-sectional study of 202 incident hemodialysis patients but this little group of patients was considered to be representative of all incident hemodialysis patients in 2002 in the United States Renal Data System. In this group of patients the prevalence of the metabolic syndrome was almost 70%. Of course, including a large proportion of patients with Type 2 diabetes.
A Chinese population of 235 hemodialysis patients, there the prevalence of metabolic syndrome was 46%and the metabolic syndrome carried a significant risk for hospitalisation but this risk was not as great or as strong as hypoalbuminemia.
In Australia 200 patients with stages 4 and 5 of CKD were followed. The prevalence of metabolic syndrome was 30.5%. This syndrome was independently predicted by age, by PD treatment and ethnicity.

Slide 23

So, looking at all this one asks does the term ‘metabolic syndrome’ have a value in clinical practice?
I think there is a problem that in a number of studies metabolic syndrome does not predict Type 2 diabetes or cardiovascular disease with greater power than some of their individual components. Also one problem is there doesn’t seem to be one metabolic syndrome. In view of the uncertainty about the relative importance of the various components it doesn’t seem meaningful to define very strict criteria for the metabolic syndrome.
So in my view and I share it with many others the metabolic syndrome has no real scientific value and it should not be used as a diagnosis put on a patient. It’s not a good term for predicting cardiovascular disease or CKD. But the term metabolic syndrome might have some pedagogic value and it may be used as a description of a rather diffusely defined cluster of metabolic risk factors to raise awareness with the public and individual patients for lifestyle intervention. While at the same time individual risk factors must be treated optimally as well as we can.

Slide 24

Thank you.