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 may well be outdated and require much more consideration than has been given to this issue in the past.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

Calories are the currency of weight management and any weight loss diet has to offer fewer calories than the body needs.

However, the means by which this caloric deficit is best achieved remains an area of continuing debate. While the proponents of ketogenic low-carb diets cite the greater ease of lowering weight, proponents of low-fat diets extol the putatively greater benefits on lipid profiles.

Nevertheless, previous studies have clearly shown that in the end both strategies lead to the same amount of weight loss, even if the low-carb approach may initially seem more effective.

This observation is once again confirmed in a new study by William Yancy Jr and colleagues from the Veterans Affairs Medical Centre, Durham, NC, published in the latest issue of the Archives of Internal Medicine.

In this study 146 overweight or obese outpatients (mean age 52 yrs) were randomized to either a ketogenic low-cab diet (initially <20 g of carbohydrate daily) or the lipase inhibitor orlistat (120 mg TID) combined with a low-fat diet (<30% energy from fat, 500-1000 kcal/d deficit) over 48 weeks.

Of the initial participants, 79% completed the low-carb arm whereas 88% completed the orlistat plus low-fat diet. Weight loss was similar between the groups, with participants losing around 9% of their initial body weight on either diet.

While the low-carb diet appeared to have a more beneficial impact on blood pressure, the orlistat low-fat combination appeared to have a greater beneficial impact on LDL-cholesterol.

However, in the end it is probably fair to say that both approaches led to more or less similar improvements in body weight and related risk measures, showing once again that this is probably not so much about which diet is more effective as it is about which diet works best for you.

Thus, in clinical practice it is likely that some patients will find it easier and preferable to severely restrict their carb intake, while others may find it easier to reduce their calories from fat by taking orlistat and reducing the fat in their diet.

The bottom line in both case is that the benefits will only persist as long as the participants stay on their respective diets or treatments. This makes it even more critical that patients chose the strategy that works best for them and that they are most likely to stay on in the long term.

Remember, neither diet is likely to “cure” obesity. As with all obesity treatments, when the interventions stop the weight comes back.

AMS
Edmonton

Yesterday, the European Medicines Agency recommended the suspension of marketing authorisation for sibutramine across the European Union. Sibutramine is marketed as Reductil, Reduxade, Zelium and other tradenames in the European Union.

This recommendation comes after completion of a safety review of the Agency’s Committee for Medicinal Products for Human Use (CHMP). The review was prompted by data from the 10,000-patient Sibutramine Cardiovascular Outcome (SCOUT) trial , which showed an increased risk of serious, non-fatal cardiovascular events, such as stroke or heart attack, with sibutramine compared with placebo.

While the CHMP noted that the use of sibutramine was not in accordance with the prescribing information for most of the patients enrolled in the SCOUT study, as sibutramine is contra-indicated in patients with known cardiovascular disease and the treatment duration in the study was longer than recommended, the Committee was of the opinion that the data from SCOUT are relevant for the use of the medicine in clinical practice.

The EMA’s recommendation remains to be ratified by the European Commission

Yesterday, the US Food and Drug Administration (FDA) also released a statement that it has reviewed additional data that indicate an increased risk of heart attack and stroke in patients with a history of cardiovascular disease using sibutramine, marketed as the weight loss medication Meridia.

The release notes that while the sibutramine drug label already includes warnings against the use of sibutramine in patients with cardiovascular disease, based on the serious nature of the review findings, the FDA requested and the manufacturer agreed to add a new contraindication to the sibutramine drug label.

The contraindication will state that sibutramine is not to be used in patients with a history of cardiovascular disease, including:

- History of coronary artery disease (e.g., heart attack, angina)
- History of stroke or transient ischemic attack (TIA)
- History of heart arrhythmias
- History of congestive heart failure
- History of peripheral arterial disease
- Uncontrolled hypertension (e.g., > 145/90 mmHg)

The FDA release further states that patients currently using sibutramine should talk with their healthcare professional to determine if continued use of sibutramine is appropriate and discuss any questions they may have about their treatment.

The final results of the SCOUT study have yet to be published in a peer reviewed journal.

AMS
Edmonton, Alberta

Disclaimer: I have received speaking, consulting and research support from Abbott, the maker of sibutramine and am on the Executive Steering Committee of the SCOUT study.

When the adipocyte-derived protein leptin was first discovered almost 20 years ago, it was touted as a possible “cure” for obesity. This idea never proved clinically effective with the exception of rare cases of genetic leptin deficiency.

However, as reviewed by Theodore Kelesidis and colleagues from Harvard Medical School, Boston, MA, in the latest issue of the Annals of Internal Medicine, there are a number of other interesting uses of leptin treatment that may well prove to soon be clinically relevant.

Thus, while circulating leptin levels certainly serve as a gauge of energy stores, thereby directing the regulation of energy homeostasis, neuroendocrine function, and metabolism, it appears that leptin’s physiological role is more as an indicator of energy deficiency, rather than energy excess.

Thus, decreases in leptin levels (as see with caloric restriction, weight loss, or loss of adipose tissue as in lipodystrophy) may mediate adaptation by driving increased food intake and directing neuroendocrine function to converse energy, such as inducing hypothalamic hypogonadism to prevent fertilization (as seen with anorexia or excessive exercise).

Currently a number of studies are exploring the role of leptin (particularly long-acting leptin homologues, e.g. metreleptin) in helping prevent weight regain in patients with intentional weight loss.

Replacement of leptin in physiologic doses also restores ovulatory menstruation in women with exercise-induced hypothalamic amenorrhea and improves metabolic dysfunction in patients with lipoatrophy, including lipoatrophy associated with HIV or highly active antiretroviral therapy.

Thus, although leptin treatment may not be an effective way to promote weight loss, it may well prove to have a number of clinical applications that may be relevant to weight management and treating the complications of excessive weight loss or lipodystrophy.

AMS
Edmonton, Alberta

I have previously blogged about the unfortunate effect of atypical antipsychotics on body weight and on the possible strategies that may be effective in dealing with this important complication of psychiatric treatment.

As the number of children and adolescents diagnosed with and treated for psychiatric disorders continues to increase, the use of these medications in this population is of growing concern.

The extent to which atypical antipsychotic medications promote weight gain and increase cardiometabolic risk in children and adolescents was recently addressed by Christoph Correll and colleagues from the Zucker Hillside Hospital, Glen Oaks, NY, in a paper published in JAMA.

The researchers analysed data from a nonrandomized Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) cohort study, conducted between December 2001 and September 2007.

Of 505 youth aged 4 to 19 years with 1 week or less of antipsychotic medication exposure, 338 were enrolled (66.9%) of which 272 had at least 1 postbaseline assessment (80.5%), and 205 patients who completed the study (60.7%). Patients were treated for mood spectrum (48%), schizophrenia spectrum (30%), or disruptive or aggressive behavior (22%) disorders.

Treatment with aripiprazole, olanzapine, quetiapine, or risperidone for 12 weeks resulted in weight gain ranging between 8.5 kg with olanzapine (n = 45) and 4.4 kg with aripiprazole (n = 41). A small control group (that refused or were non-adherent with treatment) had no weight gain during the follow up period.

Olanzapine, quetiapine and risperidone adversely effected plasma lipids, while there were no changes in these parameters with aripiprazole or in the untreated controls.

This study not only highlights the clinically important effect of these antipsychotic compounds on body weight but also suggests that there may be important differences in the magnitude of these effects with different medications.

While these adverse effects should certainly not deter from the use of these compounds where absolutely indicated (given the considerable morbidity associated with severe psychiatric disorders), avoidance of weight gain remains an important challenge that needs to be addressed.

AMS
Edmonton, Alberta