Of course, obesity is associated with a wide range of health problems like high blood pressure, diabetes, arthritis, or reflux disease, all of which may all require pharmacological treatment. But this is not what this post is about.

Rather, this post is actually about the question whether or not larger patients need higher doses of medications to have an optimal treatment effect.

This topic was recently discussed by Matthew Falagas and Drosos Karageorgopoulos in a Lancet article that specifically addresses the issue of dose adjustments for antimicrobial agents in larger patients.

As the authors point out, body size is routinely considered in the optimization of drug therapy in oncology, anaesthetics and pediatrics. However, there remains a paucity of data on the optimal dosing of pharmacological agents for most of the drugs we use in clinical practice.

Thus, although regulatory agencies regularly demand special pharmacokinetic studies in children, elderly prople and patients with renal or hepatic impairment, no such studies are demanded for obese or even severely obese patients.

Requiring such studies would at least make theoretical sense as, conceivably, obesity can affect drug absorption, distribution, metabolism and clearance. Furthermore, it is obvious that body composition can particularly affect the disposition of lipophilic compounds. Obese patients are also likely to have comorbiditiesthat can affect these parameters (e.g. fatty liver disease) and are much more likely to be on multiple medications that can make drug-drug interactions problematic.

In short, as pointed out by Falgas and Karageorgopoulos the one-size-fits-all strategy for antimicrobial agents (and other drugs?) may well be outdated and require much more consideration than has been given to this issue in the past.

AMS
Winnipeg, Manitoba

Despite the wide-spread concern about the health impact of the childhood obesity epidemic, there is actually not much data that directly shows how this excess weight may affect mortality.

Such data is now available at least for native American kids, from a study by Paul Franks (National Institutes of Health, Phoenix, AZ) and colleagues, just published in the New England Journal of Medicine.

The researchers analysed data from a cohort of 4857 American Indian (Pima or Tohono O’odham Indian) children without diabetes (mean age, 11.3 years) born between 1945 and 1984.

During a median follow-up period of around 24 years, death rates from endogenous causes among children in the highest quartile of BMI were more than double those among children in the lowest BMI quartile.

Similarly, rates of death from endogenous causes among children in the highest quartile of glucose intolerance were 73% higher than those among children in the lowest quartile and childhood hypertension was significantly associated with a 60% increased risk of premature death from endogenous causes.

Thus, at least in native Americans, childhood obesity is a significant risk factor for premature death - certainly a warning for those who believe that early obesity is something you can simply grow out of.

Given the raging epidemic of childhood obesity amongst the First Nations, Inuit, and Métis populations in Canada, these data should certainly prompt decisive action to address obesity amongst its native peoples.

AMS
Edmonton, Alberta

Obesity is often described as a state of low grade inflammation. Activated macrophages (white blood cells) in adipose tissue play an important role in this inflammatory response by secreting a number of pro-inflammatory molecules (cytokines) that can promote the development of insulin resistance and other complications of obesity.

Previous studies have shown that the “glitazone” class of antidiabetic agents can suppress inflammatory macrophage activation and can also increase the expression of an DGAT1 (triacylglycerol (TG) synthesis enzyme acyl CoA:diacylglycerol acyltransferase 1), an enzyme that makes it easier for fat cells and macrophages to store excess fat.

Now a paper by Suneil Koliwad and colleagues from the Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA, published in this weeks’ issue of the Journal of Clinical Investigation, provides further evidence that increasing activity of DGAT1 in adipocytes and macrophages may protect animals from the pro-inflammatory effects of obesity.

The researchers found that although mice overexpressing DGAT1 in both macrophages and adipocytes were more prone to weight gain, they did not show signs of the inflammatory response commonly seen with diet-induced obesity.

Through a series of experiments, the researchers were able to establish that DGAT1 is indeed necessary to protect against this inflammatory response, thereby raising the question of wether stimulation of this enzyme may also protect against the complications of obesity in humans.

Thus, although this research may not lead to new ways of preventing or reducing obesity, it may open new avenues for attenuating some of the health consequences related to excess weight.

AMS
Copenhagen, Denmark

Although excess weight is well known to substantially increase the risk for heart disease, we and others have consistently reported that obese patients with heart failure actually live longer than those who are normal weight or skinny.

This obesity “paradox” obviously begs the question of whether or not weight loss is something that you would actually recommend to someone who is obese and has heart failure - if being obese when you have heart failure, wouldn’t losing weight make things worse?

Believe or not, there are almost no studies addressing the impact of intentional weight loss on heart function. The few available studies are largely limited to small series of patients who underwent bariatric surgery, where weight loss does show marked improvements in heart function.

But can similar effects be achieved with dietary weight loss?

This is exactly the question that will be addressed by a study to be performed in collaboration with researchers at the Mazankowski Alberta Heart Institute. The study will include twenty severely obese individuals with heart failure, who will undergo intentional weight loss using a standardized low calorie diet (OPTIFAST 900). Their cardiac function and other parameters will be carefully measured and will hopefully show significant improvements in hemodynamic function and exercise capacity.

The study is funded with a $250,000 grant provided by the Alberta University Hospital Foundation and is due to be completed within three years (if not sooner).

To watch a video on this study as reported on CTV News click here or to read more about the background on CBC News click here.

AMS
Edmonton, Alberta

Yesterday, I blogged about the fact that obesity may promote the development of kidney disease by making these organs more sensitive to even a moderate increase in blood pressure.

Today, I cite an article by Sankar Navaneethan and Hans Yehnert published in the latest issue of the Surgery for Obesity and Related Diseases (SOARD) suggesting that bariatric surgery may halt and perhaps even reverse progressive loss of renal function in severely obese patients with stage 3 chronic kidney disease (glomerular filtration rate [GFR] 30–59 mL/min/1.73 m2).

In this retrospective study of 25 patients with average BMI at surgery of around 50 and a mean GFR of 47.9 mL/min/1.73 m2, surgery reduced BMI to 38.4 at the end of 6 months and to 34.5 kg/m2at the end of 12 months. This reduction in body weight was accompanied by a significant reduction in blood pressure and an increase in GFR at 6 months to 56.6 and a further increase at 12 months to to 61.6 mL/min/1.73 m2.

These findings are in line with several previous reports of improvement in renal function with weight loss but systematic prospective intervention studies of weight loss in obese patients with impaired renal function are unfortunately still lacking.

Nevertheless, it appears that kidney function may well improve with weight loss and that this treatment option should be considered in obese patients presenting with chronic kidney disease.

AMS
Edmonton, Alberta