Although, in the end I spent less than 24 hrs in the Emirates, one of the highlights of attending the 1st International Abu Dhabi Diabetes Conference, was the opportunity to once again hear David Cummings (Seattle) speak about how bariatric surgery can lead to the remission of type 2 diabetes. Cummings’ talk certainly provided plenty of food for thought on my long flight back to Canada.

As outlined in a newly released Diabetes Surgery Position Statement published in the latest issue of the Annals of Surgery, surgical approaches may well prove to be the treatment of choice in carefully selected patients with poorly controlled type 2 diabetes and a BMI greater than 30.

While the authors of the Statement emphasize the need for more clinical trials to investigate the future role of surgery in diabetes treatment, they also call for further investigations on the mechanisms of surgical control of diabetes (which are far from being fully understood).

Although weight loss itself clearly plays a significant role in the reversal of diabetes generally seen with bariatric surgery, with gastric bypass surgery, this reversal of diabetes often precedes the weight loss and there are likely neuroendocrine consequences to allowing food to bypass the duodenum that may substantially affect glucose metabolism (including regeneration of pancreatic beta-cells).

Thus, a better understanding of exactly how gastrointestinal surgery “cures” diabetes, will hopefully also open new avenues for pharmacological treatments that can mimic the effects of surgery in these patients.

Indeed, certain gut-hormones, which are known to be dramatically affected by gastric bypass surgery (e.g. GLP-1), have already been shown to have a beneficial effect both on diabetes and weight management (e.g. liraglutide).

Health professionals who want to learn more about this topic should consider attending the upcoming First Canadian Summit Metabolic Surgery for Type 2 Diabetes to be held in partnership with the Canadian Obesity Network and the Canadian Diabetes Association at the Hôtel Le Centre Sheraton, Montréal, May 6-7, 2010.

To watch a recent episode of 60 Minutes on CBS, which features interviews with Cummings and others discussing the surgical approach to type 2 diabetes, click here.

Very much appreciate hearing from my readers on their thoughts regarding whether or not diabetes surgery (vs. lifelong medications or injections) will significantly change how we treat diabetes in the future.

AMS
Edmonton, Alberta

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