Dr. Sharma's Obesity Notes

Bariatric surgery can profoundly affect how the body absorbs medications - this issue, however, remains largely understudied.

In a paper, just published in the Journal of Antimicrobial Chemotherapy, we examine the effect of gastric bypass surgery, a procedure that circumvents the upper gut on the bioavailability (absorption) of azithromycin, a widely used treatment for community-acquired infections.

We performed single-dose pharmacokinetic studies in 14 female post-gastric bypass patients and 14 sex- and body mass index (BMI)-matched controls (mean age 44 years and BMI 36.4).

Azithromycin concentrations, following the administration of two 250 mg tablets were about 30% lower in gastric bypass patients compared with controls.

This finding suggests that there may be a substantial risk for treatment failure with this antibiotic in and clinicians should consider dose modification and/or closer clinical monitoring of gastric bypass patients receiving azithromycin.

AMS
Calgary, Alberta

Padwal RS, Ben-Eltriki M, Wang X, Langkaas LA, Sharma AM, Birch DW, Karmali S, & Brocks DR (2012). Effect of gastric bypass surgery on azithromycin oral bioavailability. The Journal of antimicrobial chemotherapy PMID: 22577100

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Relative Size Illusion

Regular readers may recall previous posts on the widespread reporting of weight loss in surgical studies as ‘excess weight loss’ - a meaningless number based on outdated concepts of ‘ideal weight’. In fact, not only is there is little correlation between the amount of weight lost and improvements in post-surgical morbidity and mortality but there is nothing to suggest that using this measure does anything more than amplify the numbers - after all a rather remarkable 60% EWL is little more than 20% of initial weight - but of course 60% sounds so much better.

I was therefore happy to see that last week, at the FDA hearing on obesity devices, according to Close Concerns:

“There was nearly unanimous support for using percentage of total body weight rather than percentage of excess weight loss as a study endpoint. Panelists cited the “significant flaws” in excess weight loss, especially the challenge of applying it to individuals with lower BMIs. In contrast, many believed that using percentage of total body weight loss provided a more valid metric for people at both high and low BMIs.”

Hopefully, surgeons and surgical device makers will take note and comply with what I am hoping the FDA will from now on like to see in all future submissions - strict reporting of percentage of ‘total weight loss’ rather than the confusing, arbitrary, and scientifically unsound use of ‘excess weight loss’, which I fear the surgeons may find hard to abandon.

AMS
Brooks, Alberta

Yesterday, I noted that, although in the short term, bariatric surgery may be the preferred treatment for individuals with diabetes, the vast majority of people with this condition will have little hope of ever being handed this ‘parachute’.

For most, medical management of diabetes will be the best they can hope for.

But hope they can - as shown in a report from the randomized controlled Look AHEAD trial (now in its 5th year) by Jack Rejiski and colleagues, published in the New England Journal of Medicine.

This paper reports the impact of the ongoing intensive lifestyle intervention, aimed at achieving and maintaining a ~7% weight loss together with increased physical activity, to a diabetes support-and-education program in over 10,000 overweight or obese adults between the ages of 45 and 74 years with type 2 diabetes.

At year 4, participants randomised to the lifestyle-intervention group had a relative reduction of 48% in the risk of loss of mobility, as compared with the support group. Both weight loss (approximately 6.5%) and improved fitness (as assessed on treadmill testing) were significant mediators of this effect.

Thus, as the authors conclude, even modest weight loss together with improved fitness slowed the decline in mobility in overweight adults with type 2 diabetes even over this rather short four years of the study.

While these results may appear modest in the light of yesterday’s report on surgical outcomes, let us remember, that we are here talking about a study with over 10,000 participants, compared to the just over 200 participants in the surgical trials (not to mention the remarkably longer follow-up of this ‘lifestyle’ study).

This is the reality of the situation - while surgery can ever only be a solution for a vanishingly small proportion of the over 300 million people living with diabetes today, the lifestyle interventions of the Look AHEAD trial, with its significant and clinically meaningful outcomes, could indeed be offered to virtually anyone, who should happen to develop this condition.

Let us also remember, that much of the infrastructure and personnel that would need to be put in place to assure the long-term outcomes of bariatric surgery, are not all that different from what would be needed to better manage diabetes.

AMS
Edmonton, Alberta

Rejeski WJ, Ip EH, Bertoni AG, Bray GA, Evans G, Gregg EW, Zhang Q, & Look AHEAD Research Group (2012). Lifestyle change and mobility in obese adults with type 2 diabetes. The New England journal of medicine, 366 (13), 1209-17 PMID: 22455415

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In 2003, Gordon Smith and Jill Pell from the University of Cambridge, UK, published a thought-provoking paper in the British Medical Journal, on the effectiveness of parachute use to prevent death and major trauma related to gravitational challenge.

Despite an exhaustive search of the medical literature, they were unable to identify any randomised controlled trials of parachute interventions to avoid death as a result of plummeting earthward from a great hight.

Notably, the researchers pointed out (rather harshly, perhaps) that,

“As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.“

I remind readers of this paper in the context of two randomised controlled trials (one from the US, the other from Italy) on the effect of bariatric surgery on the resolution of type 2 diabetes recently published in the New England Journal of Medicine.

Without going into details of the trials or their findings, it suffices to point out that both studies turned out to be overwhelmingly favourable to surgery.

Thus, at 12 months, the US study found a glycated hemoglobin level of 6.0% or less in only 12% (5 of 41 patients) in the medical-therapy group versus 42% (21 of 50 patients) in the gastric-bypass group and 37% (18 of 49 patients) in the sleeve-gastrectomy group.

Even more remarkably, the Italian investigators noted no ‘remission’ of diabetes in the medical-therapy group versus 75% in the gastric-bypass group and 95% in the biliopancreatic-diversion group.

Why do I compare the results of these two studies to the use of parachutes? Because, to anyone who is even remotely aware of the outcomes of bariatric surgery in patients with type 2 diabetes, these results are neither unexpected nor earth-shattering (pardon the pun).

Thus, I am as unimpressed by the results of these two studies, as I would have been, had they compared the ‘remission’ of obstructive sleep apnea in patients on CPAP versus bariatric surgery.

Indeed, the question was never whether or not bariatric surgery can lead to short-term (or even longer-term) ‘remission’ of type 2 diabetes compared to medical treatment - the latter, is neither aimed at nor even expected to lead to remission of diabetes - conventional medical treatment merely offers to ‘manage’ diabetes, not ‘cure’ it.

That, however, is not at all the point.

No, the questions that are really of interest when it comes to surgery in patients with diabetes are very different indeed.

1) How long does the ‘remission’ last?

2) What happens to diabetes in those, where diabetes, despite surgery, does not improve?

3) Does remission really translate into reduced diabetes complications including premature death?

4) How do the long-term complications of surgery compare to the long-term complications of diabetes?

5) How much of this improvement in diabetes is simply attributable to weight loss and how much to other mechanisms that may not require any weight loss at all?

I especially raise the last question, as it (again) turns out that neither preoperative BMI nor weight loss predicted the improvement in hyperglycemia after these procedures.

But the real question is now for health systems.

Even if surgery turns out to be the only ‘effective’ treatment and thus perhaps declared by some to be considered as the ‘first-line’ treatment for type 2 diabetes, what proportion of the world’s 300 million people living with diabetes would likely ever benefit from this treatment option? Even at 1,000,000 operations a year, it would only take about 300 years to do everyone.

Even if all bariatric surgery currently performed were limited to individuals with diabetes, current global capacity at perhaps 500,000 operations a year, addresses less than 2% of the annual global burden of this condition.

A 150% increase in availability of bariatric surgery will still leave 95% of people with diabetes untreated.

Thus, the real question for health services is to determine which 5% of people living with diabetes should be the ones to most benefit from surgery - a question left unanswered by these studies.

No doubt, for the fortunate few, surgery may provide some (temporary?) respite from diabetes.

But for those, who do not have the option of jumping off the troubled plane with a parachute, the only realistic option may be to hang on and hope for a soft landing.

AMS
Edmonton, Alberta

Hat tip to Francis Finucane for reminding me of the parachute study.

Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, Thomas S, Abood B, Nissen SE, & Bhatt DL (2012). Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes. The New England journal of medicine PMID: 22449319

Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Leccesi L, Nanni G, Pomp A, Castagneto M, Ghirlanda G, & Rubino F (2012). Bariatric Surgery versus Conventional Medical Therapy for Type 2 Diabetes. The New England journal of medicine PMID: 22449317

On day 4 of the 2nd International School on Obesity Research and Management (ISORAM), the presentations focussed on the nuts and bolts of bariatric care.

The day was kicked off with a presentation by David Urbach (Toronto) presenting an overview of economic considerations in providing appropriate bariatric care. As he pointed out, despite the fact that such analyses, necessarily, are based on a number of assumptions and may turn out different depending on the perspective (e.g. patients, health care systems, societies), most analyses strongly favour the cost-effectiveness of bariatric surgery - especially for patients with obesity related health problems like diabetes.

However, as pointed out by Scott Gmora (McMaster), the ‘elephant’ in the room, often ignored or glossed over, is the issue of the many unintended clinical outcomes that can occur following bariatric surgery. His talk focused especially on the issue of post-surgical inadequate weight loss and/or weight regain, which may occur in over 20% of all surgical patients. As he pointed out, even this number may be a gross underestimate of ‘failure’ rates, as there is very little data on long-term outcomes, as the vast majority of surgical studies routinely losing 30-40% of patients to follow-up even after just a couple of years. Thus, no one really know how high these ‘failure’ rates may be. On the other hand, there is also no clear definition of ‘failure’ - thus, for e.g. a patient with diabetes, who after surgery loses only 5% of his body weight but experiences a marked improvement in his diabetes, may be considered a ‘failure’ if the focus is on weight loss but would clearly be a ’success’ if the outcome measure is diabetes control. Given this lack of standardisation in defining outcomes and the general lack of follow-up of surgical patients, Gmora presented a framework for systematically assessing factors related to weight recidivism (pre-operative, intra-operative and post-operative).

Raj Padwal (University of Alberta) discussed the evidence for and possible utility of the Edmonton Obesity Staging System (EOSS) and why it is high time that obesity staging be incorporated into the overall estimation of obesity-related risk and eligibility for treatments.

Sean Wharton (Burlington, ON), described his experience with a model of a publicly funded bariatric service in the community, which can provide significant weight management interventions to a high volume of patients by making adequate use of a multidisciplinary team including dieticians, bariatric educators, exercise specialists, psychologists and physicians.

Bonnie MacKinnon (Sudbury, Ontario), described the challenges of setting up a bariatric regional assessment and treatment centre as part of the Ontario Bariatric Network. Patients are referred to the centre through a central process. Setting up this centre to serve North Eastern Ontario, which covers 400,000 sq km and has a culturally diverse population of 570,000, including 25% of Francophone and 10% Aboriginal, provided significant learnings. Building relationships with the community, media, host hospital and community hospitals were instrumental in establishing a successful clinic. Futures goals for the Sudbury RATC include continued outreach to clinicians and patients in the region offering support and education in bariatric surgical care and implementation of a non-surgical obesity program.

Additional talks included a presentation by Daniel Birch (University of Alberta) on surgical outcomes in a publicly funded health care system, a talk by Keith Brewster (Kelowna, BC) on the establishing a LABG program in a community setting, a review of nutritional aspects of bariatric management by Jacqueline Jaques (Irvine, FL), and my take on the importance of exploring the whys of obesity rather than just the whats.

AMS
Lake Louise, Alberta