Arya M. Sharma, MD

Prof. Raymond Négrel, Director of the Faculty of Sciences, University of Nice-Sophia Antipolis.

Following our 1999 report on the existence of a local renin-angiotensin system in human adipose tissue, we thought it appropriate to write a review on the now rapidly accumulating evidence from human and animal studies on the physiology and potential health-related effects of this system, especially in relationship to cardiometabolic problems (although this term had yet to coined).

So, in 2000, I invited Raymond Negrel from the Centre de Biochimie, Université de Nice-Sophia Antipolis, Nice, France, to join Stefan Engeli and myself in co-authoring this paper for HYPERTENSION.

At the time, renin-angiotensin system had already long been recognized as an important regulator of systemic blood pressure and renal electrolyte homeostasis. In addition, it had become evident that local renin-angiotensin systems in a wide range of tissues, including the heart, blood vessels, and the brain, may play a role in pathological changes of organ structure and function by modulating gene expression, growth, fibrosis, and inflammatory response.

With regard to the function of this system in adipose tissue, we reviewed the literature on the emerging evidence for a role in adipogenic differentiation and in the regulation of body weight.

We also discussed how such changes in adipose-tissue renin-angiotensin could affect systemic activity of this system, thereby influencing blood pressure.

We concluded our review by noting that:

“..future studies with more carefully described phenotypes are necessary to conclude whether obesity (by stimulation of adipogenic differentiation) and hypertension are associated with changes of renin-angiotensin system activity in adipose tissue. If so, the physiological relevance of this system in animal models and humans may warrant further interest.”

Stay tuned for future posts on this topic, as my lab began addressing some of these ideas in subsequent studies.

According to Google Scholar, this paper has 312 citations to date.

AMS
Edmonton, Alberta

Engeli S, Negrel R, & Sharma AM (2000). Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension, 35 (6), 1270-7 PMID: 10856276

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Klinikum Benjamin Franklin, Charite, Berlin

Continuing in my series of past publications on obesity, today’s post is special, because it is about an event that ‘officially’ launched my shift from hypertension into obesity research and for the first time made some of the leading obesity researchers of the time aware of my very existence.

Back in 1998, I had already well-established myself in the hypertension field, being widely recognized as an expert on salt-sensitive hypertension. I was already being invited to speak at various hypertension meetings around the world and was nationally and internationally recognized for this work.

However, it would be fair to say that despite having published a few minor papers on obesity, no one in the obesity arena had ever heard of me. This was by no means surprising as, having attended a few obesity conferences by then, it was evident that few hypertension researchers interacted with obesity researchers and vice versa. Apparently, no one had yet thought of bringing the two research communities together - surprising perhaps, given the fact that obesity is the most common and powerful risk factor for hypertension.

So, perhaps for the first time demonstrating my potential talent as a ‘networker’, I decided to organize the 1st International Symposium on Obesity and Hypertension (ISOH), to which I rather cheekily ventured to invite some of the most distinguished researchers from the obesity field - cheeky, because these folks had certainly never heard of me and I was not offering any honoraria or expensive airplane tickets. I just looked for big names in obesity on the internet and sent out the invitations.

Little would I have imagined that I would assemble a roster of cutting edge ‘big names’ from both the hypertension and obesity communities for a tightly packed two day event in Berlin.

To my lay readers, the names may mean nothing, but to my professional colleagues, the following list probably reads like a ‘who-is-who’ of obesity.

W. P. T. James (Chairman, International Obesity Task Force, Aberdeen, UK) presented new data suggesting that obesity-associated comorbidity may increase rapidly in non-Caucasians with a body mass index as low as 18 kg/m2.

M. E. J. Lean (Department of Human Nutrition, University of Glasgow, UK) presented new data indicating that waist circumference (measured midway between the lowest rib and the iliac crest) is the best clinical marker of intraabdominal fat accumulation and that risks are high enough to warrant professional guidance with a waist over 102 cm in men or 88 cm in women.

R. Negrel (Centre de Biochimie, UMR6543CNRS & IFR349, Faculty of Sciences, Nice, France) and G. Löffler (University of Regensburg, Institute of Biochemistry, Regensburg, Germany), who provided convincing evidence on the presence of the renin-angiotensin system in adipose tissue.

D. L. Crandall (Wyeth Ayerst Research, Radnor, PA, USA) presented a comprehensive review, inncluding historical review of the classical experiments that identified early hemodynamic changes observed in obesity and the important role of neovascularization for the growth and development of adipose tissue.

H. Hauner (Diabetes Research Institute at the University of Düsseldorf, Germany) stressed the point that stromal cells from adipose tissue can undergo differentiation in the presence of defined adipogenic factors, including a variety of hormones and cytokines.

T. Unger (Institute for Pharmacology, Christian-Albrechts University of Kiel, Germany) presented evidence that the AT1 and AT2 angiotensin receptors may play an important role in the growth and development of a variety of tissues, including cardiac, endothelial, and neuronal cells.

F. C. Luft (Franz Volhard Clinic and Max Delbrück Center, Humboldt University of Berlin, Germany) presented the results of linkage analysis in an Arab pedigree with familial hypercholesterolemia in which heterozygous persons with normal LDL levels were identified.

T. W. Kurtz (University of California, San Francisco, CA, USA) and M. Pravenec (Czech Academy of Sciences, Prague, Czech Republic) presented data indicating that a Cd36 Mutation in some strains of spontaneously hypertensive rat may be associated with insulin resistance in these strains.

X. Jeunemaitre (INSERM U36, College de France, Paris, France) provided new evidence indicating that several polymorphisms located in the 5’ region and in the first intron of the angiotensinogen gene may contribute to the variability of plasma angiotensinogen levels.

M. L. Tuck (Veterans Administration Medical Center, Sepulveda, CA, USA) presented an up-to-date review on the role of the systemic renin-angiotensin system in obesity-related hypertension.

A. Natali (Department of Internal Medicine, University of Pisa, Italy) discussed the role of insulin resistance in obesity-related hypertension and provided data that suggesting that the sympatho-adrenergic system plays an important role in the development of obesity hypertension.

W. G. Haynes (Department of Internal Medicine, University of Iowa, Iowa City, USA), who discussed the important role of leptinergic and melanocortin influences on the sympathetic nervous system in obesity-related hypertension.

G. Seravalle (Clinica Medica, University of Milan, Italy) studied the effects of the acute blockade of corticotropin-releasing hormone (CRH) secretion induced by dexamethasone (DEX) on the sympathoexcitatory response elicited by insulin.

A. D. Strosberg (Institut Cochin de Génétique Molèculaire, Paris, France) discussed the potential role of beta-3 adrenergic receptors in the development of obesity.

S. L. H. Schiffelers (NUTRIM, Department of Human Biology, Maastricht University, Maastricht, The Netherlands) on the effects of beta 1- and beta 2-adrenoreceptors–stimulated thermogenesis and fat oxidation in lean and obese men.

S. Rössner (Huddinge University Hospital, Sweden) presented the first clinical data on a new lipase inhibitor orlistat which reduces the absorption of dietary fat by 30% and reduces weight and blood pressure.

R. Donelly (University of Nottingham, Division of Cardiovascular Medicine, Nottingham, UK) reviewed the pharmacological treatment of obesity-related hypertension.

P. G. Kopelman (St. Bartholomew’s Hospital and The Royal London School of Medicine, University of London, UK) provided an outlook of the management problems that will become apparent in the early part of the 21st century.

With this roster of leading experts, it was perhaps not surprising that we attracted over 150 attendees from over 30 countries to his ‘impromptu’ meeting.

It turns out that this was to be only the first of a total of four ISOH meetings, the last held in 2005, by which time I had not only made a name for myself in obesity (having been appointed to a Tier 1 Canada Research Chair in Cardiovascular Obesity Research and Management at McMaster University in 2002), but had also managed to build professional and personal relationships around the world that last to this day.

I also learnt important lessons that formed the very basis for eventually creating the Canadian Obesity Network, now with almost 7,000 members, by far the largest national professional obesity association in the world.

For those, who would like to read more about the symposium, the proceedings were published in Kidney and Blood Pressure Research in 2000.

For anyone who may have attended the event (or any of the subsequent ISOH meetings), I’d love to hear about your recollections of these Symposia.

AMS
Edmonton, Canada

Sharma AM, Distler A, & Hauner H (2000). International symposium on obesity and hypertension genetics and molecular mechanisms. Genetics and molecular mechanisms Kidney & blood pressure research, 23 (1), 49-72 PMID: 10567854

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As regular readers will be well aware, our recent publications on the Edmonton Obesity Staging System clearly show that BMI alone is a rather poor measure of mortality risk associated with excess weight.

Thus, according to our analyses of the NHANES population, 20-30% of obese individuals (Stage 0/1) had virtually no increased mortality risk even over the almost 20 year observation period, compared to Stage 2/3 individuals, who had substantially increased risk. Conversely, even in the ‘overweight’ category (BMI 25-30), almost 50% of individuals had a mortality risk as high of that of obese Stage 2/3 individuals.

This means that indications for obesity treatment based on BMI alone will overtreat a substantial number of obese individuals, who may have little benefit in terms of mortality, and miss an even greater number of individuals, who may well benefit from such treatments.

These observations are directly relevant to yesterday’s post on the findings of the SOS study.

As readers will recall, not only was there no relationship between BMI levels and cardiovascular outcomes in the SOS population but the overall cardiovascular risk of these participants - despite the majority being ’severely’ obese - was surprisingly low. In fact, the annual risk for experiencing an adverse cardiovascular outcome for SOS participants was well under 1% per year!

This risk level is highly reminiscent of the overall risk of Stage 0 obese individuals in our NHANES analyses.

Thus, it is readily apparent why it took almost 15 years to demonstrate any cardiovascular benefit of bariatric surgery in the SOS study - clearly this was a very ‘low-risk’ obese population.

Contrast this to the almost 3% annual cardiovascular event rate for the participants in the SCOUT trial, which, by definition, consisted exclusively of Stage 2/3 individuals. In this population, it took less than 3.5 years of even very modest weight-loss (3 to 10 kg) to significantly reduce cardiovascular outcomes.

But did surgery prove more beneficial in higher-risk participants in the SOS trial? It certainly did!

In fact, the only predictor of greater benefit of having bariatric surgery in the SOS paper proved to be having an elevated plasma insulin level - a rather crude marker of insulin resistance. It is fair to assume that these participants were in fact those with higher obesity Stages (elevated fasting insulin levels alone, would already suggest at least Stage 1 obesity).

The importance of this difference is reflected in the numbers-needed-to-treat (NNT): as low as 21 in participants with baseline plasma insulin concentrations above the median (>17.0 mU/L) and as high as 173 in individuals below or at the median (≤17.0 mU/L) insulin concentration.

This essentially means that you would need to operate only 21 patients with Stage 1+ obesity to ’save’ one life (over 15 years) but 173 Stage 0 patients for the same benefit. It does not take a financial genius to figure out that from a ‘cost-per-life-saved’ perspective, operating on Stage 1+ patients is a ‘no-brainer’ whereas operating on Stage 0 patients would (and should) probably raise some eyebrows (especially in a publicly funded healthcare system).

Thus, as we have argued before (and argued by Livingstone in an editorial accompanying the SOS paper in JAMA), it is high time we fully appreciate the “inadequacy of BMI as an indication for bariatric surgery” and begin adopting more sophisticated criteria (such as those of the Edmonton Obesity Staging System) to ensure that this treatment is available to those who are likely to benefit the most.

AMS
London, UK

Padwal RS, Pajewski NM, Allison DB, & Sharma AM (2011). Using the Edmonton obesity staging system to predict mortality in a population-representative cohort of people with overweight and obesity. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne, 183 (14) PMID: 21844111

Livingston EH (2012). Inadequacy of BMI as an indicator for bariatric surgery. JAMA : the journal of the American Medical Association, 307 (1), 88-9 PMID: 22215170

Earlier this week, I posted on an analysis of the SCOUT trial, in which we found a clear and significant ‘dose-response’ relationship between moderate weight loss (3-10 Kg) and reduced cardiovascular outcomes (including death) in the over 10,000 high-risk participants in this trial.

So far, the only data showing a reduction in overall mortality with weight loss comes from studies looking at the effects of bariatric surgery, such as the ongoing Swedish Obese Subjects (SOS) study, which just published its latest findings in the Journal of the American Medical Association (JAMA).

In this paper, Lars Sjöström and colleagues from the University of Gothenburg, Sweden, specifically examine the relationship between bariatric surgery, weight loss, and cardiovascular events in the SOS study.

Some readers may recall that the SOS study is an ongoing, nonrandomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden of 2010 obese participants who underwent bariatric surgery and 2037 contemporaneously matched obese controls who received usual care. Inclusion criteria were age 37 to 60 years and a body mass index of at least 34 in men and at least 38 in women. Surgery patients underwent gastric bypass (13.2%), banding (18.7%), or vertical banded gastroplasty (68.1%), and controls received usual care in the Swedish primary health care system.

In the present analysis, bariatric surgery was associated with an almost 50% reduction in the number of cardiovascular deaths (28 events among 2010 patients in the surgery group vs 49 events among 2037 patients in the control group) over the almost 15 years of follow-up. Similarly, there was an almost 35% reduction in the number of total first time (fatal or non-fatal) cardiovascular events (myocardial infarction or stroke, whichever came first) in the surgery group (199 vs. 234 events).

Notably, however, the investigators found no significant relationship between cardiovascular outcomes and baseline BMI or the magnitude of weight loss. This is in contrast to the SCOUT study, where we found a clear ‘dose-response’ relationship between the amount of weight lost and the reduction in cardiovascular outcomes.

Several factors may explain this lack of ‘dose-response’ relationship in the SOS study.

For one, the SOS population, despite being far more obese than the participants in the SCOUT trial, were at a much lower risk for cardiovascular complications. Thus, the annualised event rate per 1000 participants in the SCOUT trial population was more than four times that of the SOS trial (30 vs. 7). Thus, the SOS study, despite its size, duration, and heavier BMI of participants, may simply be underpowered to demonstrate a ‘dose-response’ relationship between the magnitude of weight loss and reduction in cardiovascular outcomes.

Another explanation for the lack of ‘dose response’ in the SOS vs. SCOUT trial could be related to the overall magnitude of weight loss. Thus, while average weight loss in the SCOUT trial was just under 5%, the average weight loss in SOS was about 20%. if, as many suspect, a moderate 5-10% weight loss is all it takes to significantly reduce cardiovascular risk, the average weight loss of 20% in SOS would obscure any ‘dose-response’ relationship, as all participants in SOS, so to say, were already on the highest effective ‘dose’ of weight loss.

Thus, by no means is it clear from the SOS study that losing 20% of your body weight through bariatric surgery is any better than losing just 5% of your body weight as far as cardiovascular outcomes are concerned (this is not denying any other potential benefits of bariatric surgery on diabetes, cancer, arthritis, sleep apnea, or quality of life).

Thus, in light of the recent SCOUT findings, the superiority of bariatric surgery to medical obesity treatment in reducing cardiovascular outcomes would indeed need to be demonstrated in a ‘head-to-head’ trial  - a study that is unlikely to be done anytime soon.

interestingly, the lack of relationship between baseline BMI and cardiovascular outcomes and the remarkably low overall incidence of cardiovascular complications in the SOS patients raises a number of other important issues regarding indications for surgery - a topic that I will save for tomorrow’s post.

AMS
Berlin, Germany

Sjöström L, Peltonen M, Jacobson P, Sjöström CD, Karason K, Wedel H, Ahlin S, Anveden Å, Bengtsson C, Bergmark G, Bouchard C, Carlsson B, Dahlgren S, Karlsson J, Lindroos AK, Lönroth H, Narbro K, Näslund I, Olbers T, Svensson PA, & Carlsson LM (2012). Bariatric surgery and long-term cardiovascular events. JAMA : the journal of the American Medical Association, 307 (1), 56-65 PMID: 22215166

Faithful readers will recall previous posts on the results of the SCOUT trial, in which we studied 10,744 overweight or obese subjects (≥55 years) with pre-existing cardiovascular disease and/or type 2 diabetes mellitus, who received the anti-obesity drug sibutramine plus weight management during a 6-week lead-in Period, before randomisation to continue on sibutramine (N=4906) or to receive placebo (N=4898) plus ongoing lifestyle management for another 4-5 years.

In SCOUT, participants randomised to sibutramine had an 11% higher risk of experiencing a non-fatal cardiovascular outcome (non-fatal myocardial infarction, non-fatal stroke, or resuscitated cardiac arrest) compared to the placebo group. This finding, led to the voluntary withdrawal of sibutramine in most countries (including the US and Canada).

However, as discussed before, one of the critical design features of the SCOUT trial, was that participants had to continue on medication irrespective of whether or not they actually lost weight. This is obviously very different from how an anti-obesity drug would be used in clinical practice, where no patient would likely continue taking a drug that was clearly not effective.

Thus, while the original paper, published in the New England Journal of Medicine, presented the intention-to-treat analysis, which simply compared the two treatment arms, irrespective of whether individuals lost weight or not, we have now published an analysis in Obesity, Diabetes, and Metabolism that looks at the cardiovascular outcomes in relationship to the actual weight loss during the 6-week lead-in period and over the first 12 months of the trial.

While average weight loss in the 6-week lead-in period was -2.54 kg, post-randomisation 12-month weight loss was significantly greater in the sibutramine-treated participants (-4.18 kg) compared to placebo (-1.87 kg). There was of course a considerable spread in changes in body weight both during the lead-in period and within each treatment arm post-randomisation with some participants losing little (or even gaining some) weight with others losing considerable weight (well into the 10-15% range).

The analysis clearly shows that the degree of weight loss during both the lead-in Period and through month 12 was associated with a progressive reduction in risk for the total population of experiencing ‘hard’ outcomes like having a stroke, a heart attack, or dying of other causes over the 5-year assessment.

To my knowledge, this is the first demonstration of a reduction in ‘hard’ cardiovascular outcomes with intentional (non-surgical) weight loss (3-10 kg).

Although more events occurred in the randomised sibutramine group, on average, a modest weight loss of approximately 3kg achieved in the Lead-in Period appeared to offset this increased event rate.

Thus, this analysis demonstrates that even moderate weight loss over short-term (6 weeks) and longer-term (6-12 months) periods is associated with reduction in subsequent cardiovascular mortality for the following 4-5 years even in those with pre-existing cardiovascular disease.

There are some limitations in the interpretation of these findings in that they represent a post-hoc analysis and the participants all had at least mild, moderate, or severe cardiovascular disease (EOSS 2-3). Thus, we still do not know whether or not losing weight reduces risk in obese individuals without pre-existing heart disease (EOSS 0-1).

Despite these caveats, this study certainly represents a ‘historical’ milestone in being the first to show that even modest intentional weight loss can reduce cardiovascular outcomes in a high-risk population.

Not a bad way to start off the new year.

AMS
Berlin, Germany

Caterson ID, Finer N, Coutinho W, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Legler UF, Shepherd GM, Rode RA, Perdok RJ, Renz CL, James WP, & on the behalf of the SCOUT Investigators (2011). Maintained Intentional Weight Loss Reduces Cardiovascular Outcomes: Results from the Sibutramine Cardiovascular Outcomes (SCOUT) Trial. Diabetes, obesity & metabolism PMID: 22192338