Does Obesity Kill Kidneys?

Kidneys are exquisitely sensitive to many risk factors that can also accelerate atherosclerosis and heart disease. Thus, high blood pressure and diabetes are well-established risk factors for chronic kidney disease (CKD).

Because both hypertension and diabetes are in turn linked to obesity, the question is: does obesity increase the risk for CKD?

This questions was now addressed by Meredith Foster and colleagues from the National Heart, Lung, and Blood Institute, Framingham, MA, USA, who studied the relationship between Stage 3 CKD (= moderately reduced kidney function) and BMI in the Framingham Offspring participants (n = 2,676; 52% women; mean age, 43 years) free of stage 3 CKD at baseline who participated in examination cycles 2 (1978-1981) and 7 (1998-2001). (Am J Kidney Dis)

While there was no increased risk of kindey disease in overweight participants, obese individuals had a 68% increased odds of developing Stage 3 CKD (estimated glomerular filtration rate < 59 mL/min/1.73 m(2) for women and < 64 mL/min/1.73 m(2) for men).

However, this relationship became non-significant when data was adjusted for diabetes, systolic blood pressure, hypertension treatment, current smoking status, and high-density lipoprotein cholesterol level.

The authors rightly conclude that the link between obesity and CKD is largely explained by the effect of obesity on other cardiovascular risk factors like hypertension or diabetes.

Clearly, if your excess weight is raising your blood pressure and/or making you diabetic, you may need to start worrying about your kidneys.

AMS
Edmonton, Alberta

Adolescent Obesity Kills Middle-Aged Adults

Yes, there's a childhood and adolescent obesity epidemic out there. The word on the street now is that "this is the first generation of kids, who will not outlive their parents".

But is this really true? Where is the data showing that childhood obesity is really a risk factor for early death?

This question is now answered by perhaps the largest study on this issue to date published by Tone Bjørge and colleagues from the University of Bergen, Norway, in the American Journal of Epidemiology.

Bjørge and colleagues studied the relationship between BMI (measured height and weight) and mortality in 227,000 adolescents (aged 14-19 years) recruited in Norwegian health surveys in 1963-1975. During follow-up (8 million person-years), 9,650 deaths were observed. Cause-specific mortality was compared among individuals whose baseline BMI was below the 25th percentile, between the 75th and 84th percentiles, and above the 85th percentile in a US reference population with that of individuals whose BMI was between the 25th and 75th percentiles.

Risk of death from endocrine, nutritional, and metabolic diseases and from circulatory system diseases was increased in the two highest BMI categories for both sexes. Relative risks of ischemic heart disease death were 2.9 for males and 3.7 for females in the highest BMI category compared with the reference. There was also increased risk of death from colon cancer (males: 2.1; females: 2.0), respiratory system diseases (males: 2.7; females: 2.5), and sudden death (males: 2.2; females: 2.7).

The authors conclude that adolescent obesity is related to increased mortality in middle age from several important causes.

Clearly not a good sign for what awaits our sons and daughters unless we get a hold on the obesity crisis.

AMS
Edmonton, Alberta

"Foie Gras" in Kids Risk Factor for Heart Disease

Nonalcoholic fatty liver disease (NAFLD), is now the most common cause of liver disease in children.

Although this condition is associated with insulin resistance its impact on other features of the "metabolic syndrome" is less clear.

In the July 15 issue of Circulation, Jeffrey Schwimmer and colleagues from the University of California, San Diego report on their findings from a case-control study of 150 overweight children with biopsy-proven NAFLD and 150 overweight children without NAFLD.

Children with NAFLD had significantly higher fasting glucose, insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure than overweight and obese children without NAFLD.

Not only do these findings support the notion that, as in adults, NAFLD in overweight and obese children is strongly associated with multiple cardiovascular risk factors, they also show that as in adults, weight alone is not a reliable measure of cardiovascular or metabolic risk factors in kids.

Identification of NAFLD in a child should prompt global counseling to address nutrition, physical activity, and avoidance of smoking to prevent the development of cardiovascular disease and type 2 diabetes.

AMS
Edmonton, Alberta

Epicardial Fat and Weight Loss

Increased visceral fat or "ectopic" fat deposition is associated with insulin resistance and increased cardiovascular risk.

Traditionally, the term visceral fat has been used to describe the omental and mesenteric fat located inside the abdomen. Over the last several years, this concept has been expanded to include other "ectopic" fat depots including the liver and the heart.

Recognition that the fat located around the heart can be a marker of visceral fat was pioneered by Gianluca Iacobellis, who joined me as a clinical research fellow a few years ago at McMaster University and has since been recruited to their faculty.

In this month's issue of OBESITY, Iacobellis reports on work we collaborated on just before I left McMaster to relocate to the University of Alberta demonstrating that epicardial fat is a sensitive marker of changes in visceral fat associated with weight loss.

In this study in 20 severely obese subjects who underwent a 6-month very low calorie diet weight loss program resulting in a 20% loss of original body weight, waist circumference decreased by 23% whereas epicardial fat thickness decreased by 32% of baseline.

Based on this finding, we suggest that measurement of echocardiographic epicardial fat thickness may provide an additional tool in understanding the metabolic risk associated with variation in fat distribution. Perhaps, more importantly, echocardiographic measurement of epicardial fat can serve as a simple and relatively inexpensive tool to assess changes in visceral fat with weight loss (or gain) in clinical practice.

Certainly beats simply measuring waist circumference (a rather crude surrogate measure of intra-abdominal fat) or the rather more expensive CAT or MRI study.

AMS
Edmonton, Alberta

p.s Thanks to Navneet Singh and Sean Wharton for their great help with this study and to all the patients who volunteered their time for these measurements

Does Metabolic Syndrome Predict Heart Disease?

Metabolic syndrome or syndrom X (recently refered to as Xyndrome) is the combination of abdominal obesity, high trigylcerides, low HDL cholesterol, high blood pressure and elevated levels of fasting blood glucose. This concept has been widely promoted as helping to clinically identify individuals at increased risk for heart disease.

While the concept appears intuitively sound (as all five components of this syndrome have been individually associated with increased cardiovascular risk), there is a continuing debate on whether the concept of this "syndrome" is any better in identifying individuals at risk for heart disease than looking at each individual risk factor on its own.

To address the issue of whether or not the "metabolic syndrome" is indeed a risk factor for heart disease, Naveed Sattar and colleagues from University of Glasgow examined the relationship between the metabolic syndrome and incident cardiovascular disease and type 2 diabetes in in 4812 non-diabetic individuals aged 70-82 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). They corroborated these data in a second prospective study (the British Regional Heart Study [BRHS]) of 2737 non-diabetic men aged 60-79 years. (The Lancet)

In PROSPER, metabolic syndrome was not associated with increased risk of cardiovascular disease over 3.2 years but was associated with a 4-fold increased risk of diabetes. In contrast elevated fasting glucose alone was associated with an 18-fold increased risk for diabetes.

Likewise, in BRHS, metabolic syndrome was only modestly associated with incident cardiovascular disease despite a strong association with diabetes.

Importantly, in both studies, body-mass index or waist circumference, triglyceride, and glucose cutoff points were also not associated with risk of cardiovascular disease, but all five components were associated with risk of new-onset diabetes.

The authors conclude that while metabolic syndrome and its components are associated with type 2 diabetes, they only have a weak to no association with vascular risk in elderly individuals. Their recommendation is that the clinical focus should remain on establishing optimum risk algorithms for each individual risk factor rather than lumping them together as a putative "syndrome".

Obviously, one could argue that there may still be some use for the concept of the metabolic syndrome in younger individuals, but, as discussed in this paper, the same group (and others) have also not found the metabolic syndrome to be a strong predictor of heart disease in younger individuals.

Irrespective of whether or not the concept of the metabolic syndrome is helpful, it should be remembered that obesity treatment is the only intervention that can simultaneously have beneficial effects on all five components of this syndrome. Thus, while conventional care continues to aggressively target the individual risk factors, only aggressive obesity treatment will indeed improve all features of this putative syndrome.

Unfortunately, with the exception of obesity surgery, we still lack outcome studies confirming that obesity treatment will indeed decrease cardiovascular mortality.

Remember, the assumption that losing weight (without surgery) will save lives is not based on hard evidence from randomised controlled trials. My guess is that till we have better data on this issue, physicians, payers and policy makers will continue to question the benefits of tackling obesity with the same resources and enthusiasm as for other chronic diseases.

AMS
Edmonton, Alberta

Obesity and Atherosclerosis

The next couple of days I will be at the 77th European Atherosclerosis Society Congress in Istanbul, Turkey.

Given the importance of obesity (particularly visceral fat deposition) as a risk factor for atherosclerosis, it is not surprising that there are several talks on various aspects of obesity including its pathophysiology and management at this meeting.

My own talk on Tuesday morning will be on the role of "ectopic" fat on cardiovascular risk.

Generally speaking, ectopic fat is fat that accumulates in depots other than just underneath your skin and includes fat deposits in the gut, liver, muscle and other organs.

Always important to remember that not all fat is bad and that not everyone with a couple of extra pounds of fat tissue is at risk for heart disease.

When it comes to fat and heart disease, the "where" appears to be far more important than the "how much"!

AMS
Istanbul, Turkey

Rimonabant for CAD - it's Not Just About the Heart

The heart is an important organ. Heart disease kills millions every year. Abdominal obesity is an important risk factor for heart disease. Medical treatments for obesity should help reduce cardiovascular risk.

Not surprisingly, several large studies are examining the effect of anti-obesity drugs, both old (e.g. sibutramine) and new (e.g. rimonabant), on cardiovascular morbidity and mortality.

This week, one such study reported on its results. STRADIVARIUS, a double-blind randomized controlled trial with over 800 patients conducted at 112 centres in North America, Europe and Australia was designed to determine whether treatment with 20 mg of the CB-1 antagonist rimonabant (an anti-obesity drug now available in many countries but not in Canada or the US) would reduce progression of coronary artery disease (CAD) in patients with abdominal obesity and the metabolic syndrome. Progression of CAD was measured by intravascular ultrasound (IVUS) before and after 12 to 18 months of treatment.

On average, patients on rimonabant lost 4.5 Kg and as many cms off their waistlines. HDL cholesterol, triglycerides and HbA1c levels (in patients with diabetes) improved as expected. Although the primary endpoint (change in percent atheroma volume) was not different between rimonabant and placebo, other measures of atherosclerosis appeared to change favourably. Rimonabant was well tolerated although (as expected) there were more psychiatric and gastrointestinal side effects and discontinuations in the rimonabant group.

So why, with the significant reduction in weight and risk factors were the results not more positive? The authors speculate that this may have been because patients were already receiving effective treatment for CAD (e.g. 80% of patients were on statins). Therefore showing incremental benefits of adding rimonabant would have been difficult.

The real question to ask, however, is whether or not influencing heart disease is indeed the best and most important use of an anti-obesity drug. We already have a multitude of effective medications to reduce the progression of heart disease. When used according to current guidelines, these agents can indeed markedly reduce the risk of cardiovascular disease (obviously, this risk will never be zero, no matter how good the treatment).

So is reduction in heart disease really the great "unmet need" when it comes to obesity treatment? As a bariatrician, I would say NO!

Yes, while preventing heart disease (or its progression) is perhaps one benefit of treating obesity, I can think of many other benefits that are relevant to patients battling obesity-related comorbidities for which we currently have no effective medical treatments.

My short list would include sleep apnea, osteoarthritis, hepatic steatosis, polycystic ovary syndrome, infertility, pseudo tumor cerebri and many more. Sure, these conditions may not sound as dramatic as heart disease and may be less likely to kill you, but for the people who have these problems, these conditions are very real, distressing and affecting their quality of life. If obesity treatments can help alleviate these conditions, perhaps even just limit exacerbation by helping curb further weight gain, a lot would be won.

Remember, obesity is a chronic disease with virtually 100% rezidivism. It significantly affects many aspects of mental, physical and socioeconomic health. Effective treatments for obesity are required irrespective of whether or not they also help reduce heart disease.

Unfortunately, pharma companies, regulators and payors appear obsessed with the cardiometabolic consequences of obesity and fail to see the urgent need for treating obesity-related comorbidities beyond heart disease.

So, while the results of STRADIVARIUS are nice, I'd be far more interested in whether or not rimonabant reduces obesity-related comorbidities for which we have no alternative treatments - at least that's where I'd put my research money if I had any say in the matter.

AMS
Edmonton, Alberta

Obesity Paradox also Holds in Denmark

Regular readers of this blog will have noted previous entries on the "paradoxical" reverse epidemiology of obesity and cardiovascular mortality, where risk is apparently higher in underweight compared to normal weight, overweight or even mildly obese individuals (for e.g. of previous blog entries on this click here, here or here).

Now a new Danish study by Jawdat Abdull and colleagues published in the European Heart Journal that looks at pooled data from 5 large registries with over 21,500 consecutive high-risk patients with myocardial infarction or heart failure finds essentially the same story:

After a follow-up of 10.4 years, compared with normal weight individuals (BMI 18.5-24.9) all-cause mortality was higher in underweight (BMI < 18.5) but not in overweight (BMI 25.0-29.9) or class I obese (BMI 30-34.9) individuals. Only with class II obesity (BMI 35-39.9) and higher was there a significantly increased risk for myocardial infarction and increased death risk.

This finding is very much in line with the mounting evidence that moderate overweight and mild obesity does not automatically translate into higher cardiovascular mortality in high-risk individuals with established heart disease.

As argued before, given that increased weight is a well-established risk factor for high blood pressure, diabetes, and other risk factors for cardiovascular disease, the reasons for this rather consistent "paradoxical" relationship are not clear.

Possible explanations include the idea that being underweight is a sign of general ill health and that thin people may be less able to cope with life-threatening illnesses like a heart attack at least compared to people with some extra "nutritional reserve". Of course there are a couple of more sophisticated theories out there that to me appear highly speculative (which is why I will not mention them today).

Nevertheless, in light of this "paradox", we may have to look beyond reducing cardiovascular morbidity and mortality to justify aggressive treatments of overweight and class I obesity with established cardiovascular disease - perhaps the aim of obesity treatment in high-risk individuals should simply be to prevent further weight gain rather than to reduce it?

I guess it would take intervention trials to find out - thankfully, these are already well underway.

AMS