Orlistat and Kidney Stones

Orlistat is a gastrointestinal lipase inhibitor sold as a prescription drug under the brand name Xenical and is also available in some countries (including the US) as an over-the-counter (OTC) weight-loss aid under the brand name Alli.

Orlistat has been around for almost a decade and has been extensively studied. No question, when used appropriately with recommeded dietary and lifestyle changes it aids in achieving about 5% weight loss and clinically relevant improvements in cardiometabolic risk factors (high blood pressure, low HDL, high blood sugars, etc.). As with all obesity drugs, weight is generally regained when the medication is discontinued - nothing new here!

Because the action of orlistat is limited to the gut (it is not absorbed in relevant amounts), it is promoted as not having any "systemic" side effects. The main side effects are fully explained by its impact on fat digestion and are generally limited to diarrhea, oily discharge and abdominal discomfort - unpleasant for sure, but certainly not a major health concern.

There is also some interference with the absorption of fat-soluble vitamins (ADEK) but this should not be a problem with a healthy balanced diet or proper intake of vitamin supplements. There is however, also a significant impact on lipid-soluble medications (e.g. ciclosporine A) and patients on these medication may need some readjustment of the dose.

All of the above is well known, extensively studied and not really of great concern for most patients.

But here is one side effect I'd be worrying about if I belonged to the people who tend to get kidney stones - there is a distinct chance that orlistat can increase urinary oxalate excretion thereby potentially promote formation of oxalate stones - anyone who's ever experienced a kidney colic knows exactly why this is something you want to avoid.

The cause of this potential side effect is related to the simple fact that the unabsorbed fat and bile acids resulting from the use of orlistat may react with calcium in the intestinal lumen, limiting the amount of free calcium binding with oxalate and thereby raising intestinal oxalate absorption leading to hyperoxaluria, which in turn can promote formation of oxalate stones.

This rather complex-sounding but rather straightforward state of affairs was first proposed based on a marked increase in urinary oxalate excretion observed in rats given orlistat together with a high-fat diet in a study by Renato Ribeiro Ferraz and colleagues from the Universidade Federal de São Paulo published in KIDNEY INTERNATIONAL in 2004.

In 2007, Ashutosh Singh and colleagues from the University of Tennessee described the case of a female patient with chronic kidney disease, who developed acute oxalate nephropathy with the use of orlistat (Am J Kidney Dis). Urine sediment showed abundant calcium oxalate crystals and 24-hour urine oxalate concentration was significantly elevated. Kidney biopsy showed deposition of calcium oxalate crystals within the tubular lumens. A repeat biopsy one month after discontinuing orlistat no longer showed signs of oxalate and renal function slowly recovered to baseline.

Now, in this month's issue of OBESITY, Kemal Sarica and colleagues from the Memorial Hospital in Istanbul, Turkey, report the data from a study in 95 obese patients (57 men, 38 women) randomly assigned to treatment with orlistat for 6 months vs. no specific medication. In the treatment group, two-thirds of patients showed a marked increase in urinary oxalate excretion at 3 months, which largely persisted at 6 months. Although no kidney stones were noted, the authors commented that the increase in oxalate excretion would have been enough to promote oxalate stone formation in susceptible individuals.

Nothing dramatic here - unless of course you are someone who happens to be at risk for oxalosis and oxalate kidney stones.

If you are, perhaps best to avoid orlistat or at least cut down on the concomitant use of high oxalate foods like rhubarb, spinach, strawberries, chocolate, wheat bran, nuts, beets, and tea and drink plenty of water.

AMS
Edmonton, Alberta

Exhaustion Promotes Weight Gain

OK, we know stress, lack of time, low socioeconomic status, poor locus of control and poor sleep promote obesity - but here is a new one (at least for me): Vital Exhaustion.

The term Vital Exhaustion (VE) has three defining characteristics: (1) feelings of excessive fatigue and lack of energy, (2) increasing irritability, and (3) feelings of demoralization.

People often attribute these feelings to overwork, or to problems at work or in other important life areas that the person has not been able to solve, or to a real or symbolic loss. Therefore, it has been suggested that VE is a mental state at which people arrive when their resources for adapting to stress are broken down.

Now Maria Bryant and colleagues from the University of Leeds, UK in a paper just out in OBESITY, examined the relationship between VE and BMI cross-sectionally and after 3 and 6 years of follow-up among the 13,727 participants in the Atherosclerosis Risk in Communities (ARIC) study.

BMI was significantly higher among both white and African-American men and women in the highest VE quartile compared to those with no VE. Similarly, high VE at baseline was associated with higher BMI 3 and 6 years later. Baseline VE predicted future excess weight gain in white men and women, but not in African Americans.

Clearly, if this relationship is causal, identifying the factors contributing to VE and addressing them may help prevent and reduce the burden of obesity - certainly easier said than done.

Anyone who thinks we will solve the obesity crisis by handing out diet plans and chasing people around the block are kidding themselves.

AMS
Edmonton, Alberta

How much protein is enough?

The recommended dietary allowance (RDA) is an estimate of the minimum average dietary intake level that meets the nutrient requirements of nearly all (~97%) healthy individuals.

According to this recommendation, the RDA for protein is 0.8 g/kg/d

Interestingly, as pointed out in a recent commentary by Robert Wolfe and Sharon Miller from the University of Arkansas published in the June 25 issue off JAMA, the term “recommended dietary allowance” is misleading as it is often misinterpreted as being the “optimal” rather than the “minimal” dietary requirement.

In fact, as illustrated in the commentary, if protein requirements are calculated based on a recommended proportion of energy intake [i.e. 10 to 35%], for a 70 Kg man requiring 3067 kg calories per day, 10% of energy as protein would translate into a protein intake of 0.95 g/kg/d whereas 35% of energy intake would translate to 3.3 g/kg per day. These values are obviously substantially higher than the RDA.

As blogged before, given the importance of maintaining appropriate protein intake to maintain muscle mass, strength and function, the issue of ensuring adequate protein intake during a caloric restricted diet becomes even more challenging. This means that caloric restricted diets need to at least provide a protein intake at the higher end of the Dietary Reference Intakes [DRI] or around 35% of total caloric intake and should perhaps err on the side of too high rather than too low.

The issue of maintaining appropriate protein intake is particularly important as close monitoring of body composition to detect disproportionate loss of lean body mass during weight loss is not routine part of patient monitoring during obesity treatment.

Perhaps, as recommended by Wolfe and Miller, the term “recommended dietary allowance” should be replaced by the term “minimal dietary requirement” to more accurately reflect the functional definition of RDA and avoid confusion regarding what is considered adequate protein intake.

AMS
Edmonton, Alberta

No Food For the Lazy!

Yesterday, newspapers reported widely about the UK conservative leader David Cameron calling on the obese, the idle, and even the poor to accept some responsibility for their plight.

According to Cameron, society has become "far too sensitive" to people's feelings, with no one prepared to say "what needs to be said." "We talk about people being 'at risk of obesity' instead of people who eat too much and take too little exercise".

Great stuff! So all fat people eat too much and are lazy - they deserve their plight! In other words, let's stop coddling them and let's certainly not bother providing them with any health services for their plight.

Perfect. Let's next stop providing services for all smokers who get heart attacks or cancer, no more trauma surgery for anyone who gets injured driving above the speed limit or, God forbid, gets run over jay walking. No more health services for anyone coming down with influenza who did not get his flu shot, no more medical freebies for people spraining their ankles at sports, and obviously definitely no more medical help with "lifestyle diseases" like diabetes, high cholesterol, hypertension, osteoporosis, osteoarthritis and back pain.

Everyone is the master of their own destiny.

Thank you Mr. Cameron for saying what needed to be said.

Anyone feeling depressed? Suck it up!

AMS
Edmonton, Alberta

Proconvertase Gene Linked to Obesity

As unequivocally documented by twin studies, obesity is one of the most heritable complex traits. However, so far only a handful of genes that may play a role in the common "garden variety" of obesity (i.e. not just the rare monogenic forms) have been identified .

This week, a large research team led by Philippe Froguel (Picture) that included scientists from France, Denmark, Sweden, Germany and the UK report in Nature Genetics that relatively common variants of the PCSK1 gene, which codes for the proconvertase enzyme are associated with higher BMI. This enzyme is responsible for producing fully functioning versions of hormones such as insulin and glugagon that play important roles in carbohydrate metabolism but also for melanocortin, a key regulator of satiety.

Although the identified variants of the PCSK1 gene cause only relative minor functional changes in this enzyme, the effect on the relevant hormones is quite significant.

Obviously, no single gene or variant thereof can account for all of obesity and there is no reason to believe that all obesity is the same. Rather, it is clear that the heritability of obesity must be due to the distribution of a large number of variants of numerous genes in the population.

So when do we begin using genetic testing in our obesity clinics - not for a while I am guessing, i.e. till we can actually show that specific genes also predict better (or worse) outcomes with specific treatments.

In the dark, all cats are grey.

AMS
Edmonton, Alberta

Germany Wakes up to Obesity

As elsewhere in Europe, obesity is on the rise in Germany. According to government statistics, two-thirds of all German men between the ages of 18 and 80 are overweight and almost half of all women have a weight problem. These numbers add up to about 37 million adults and 2 million children and teenagers suffering from some kind of weight related disorders.

In response, the German government has now embarked on a new obesity initiative prepared by Health Minister Ulla Schmidt in cooperation with Food, Agriculture and Consumer Protection Minister Horst Seehofer. The program's initiative is to cut diseases related to obesity drastically by the year 2020, and foresees spending 30 million euros ($46.7 million) over the next two years.

As everywhere else, in Germany too, the government recognizes that the epidemic is not only a result of poor nutritional habits and lack of exercise but also wide-ranging societal and infrastructural factors. It therefore calls on politicians, scientists, health-care providers, unions and the food industry to help educate and promote healthier lifestyle approaches. As one may guess the ideas include: education on healthy eating and physical activity, tougher standards on school food programs, better product labeling by the food industry, reduced advertising by the makers of sweets and junk food that target children, i.e. essentially the usual list of initiatives.

As everywhere else, in Germany too, the government largely ignores one major consequences of the fact that 37 Million Germans are already living with this chronic disease, namely that this also calls for an immediate need to provide improved access to evidence-based obesity treatments with expansion of the resources to do so.

As in most other countries (the UK being a remarkable exception), access to professional obesity treatment that includes behavioural therapy, anti-obesity medications and surgery remains limited to a ridiculously small number of individuals, mostly those who can afford "private" payments for these services.

As I have blogged before - promoting obesity prevention (and hoping for these to kick in) should not be an excuse to deny obesity treatments to those already affected by this condition.

AMS
Edmonton, Alberta

p.s. incidentally, my blog is now also available in German

Image Rainer Zenz

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