Bruno Halpern

Safety assessment of FDA-approved (orlistat and lorcaserin) anti-obesity medications

Introduction: Options for treating obesity remain limited despite it being a chronic, recurrent and morbid condition. New drugs that are proposed for its treatment encounter strong reluctance by regulatory agencies and many doctors. Areas covered: This review will focus on the safety of an older drug, orlistat (the only one still approved in the European Union) and a newer recently FDA-approved one, lorcaserin. Both are approved as long-term monotherapy for obesity in the United States of America and they have demonstrated median weight loss of nearly 3% over placebo. Expert opinion: Research, development and approval of new anti-obesity drugs are necessary for improved management of this chronic condition. Orlistat and lorcaserin are two FDA-approved drugs with limited overall efficacy. Nevertheless they are useful weapons for at least some obese individuals. Orlistat has a long and solid safety profile, whereas the safety of lorcaserin is still a matter of debate, mainly due to a lack of long-term data. However, lorcaserin’s selective agonism on 5HT2c serotonin receptors diminishes concerns about valvulopathy associated with other serotonin agonists, such as fenfluramine.

Combinations of Drugs in the Treatment of Obesity.

Obesity is a chronic disease associated with excess morbidity and mortality. Clinical treatment, however, currently offers disappointing results, with very high rates of weight loss failure or weight regain cycles, and only two drugs (orlistat and sibutramine) approved for long-term use. Drugs combinations can be an option for its treatment but, although widely used in clinical practice, very few data are available in literature for its validation. Our review focuses on the rationale for their use, with advantages and disadvantages; on combinations often used, with or without studies; and on new perspectives of combinations being studied mainly by the pharmaceutical industry.

Why are anti-obesity drugs stigmatized?

Obesity is a common and morbid disease, but its treatment remains far from ideal. Many doctors, regulatory agencies, media outlets and patients consider lifestyle modification as the only possible intervention. Pharmacological agents, although with limitations, are useful weapons but are highly stigmatized. Some reasons for this stigma are discussed in this editorial and include: the failure of short-term medication use to achieve long-term results (due to the chronic and recurrent condition of obesity); common perception of obesity as a lifestyle choice; difficulty to treat obesity in the primary care setting; less than desired weight-loss results with medications; misuse of medications for cosmetic reasons; and unfavorable history of other anti-obesity drugs that were withdrawn in previous decades.

Brown adipose tissue: what have we learned since its recent identification in human adults

Brown adipose tissue, an essential organ for thermoregulation in small and hibernating mammals due to its mitochondrial uncoupling capacity, was until recently considered to be present in humans only in newborns. The identification of brown adipose tissue in adult humans since the development and use of positron emission tomography marked with 18-fluorodeoxyglucose (PET-FDG) has raised a series of doubts and questions about its real importance in our metabolism. In this review, we will discuss what we have learnt since its identification in humans as well as both new and old concepts, some of which have been marginalized for decades, such as diet-induced thermogenesis.

Fixed-dose combination of phentermine-topiramate for the treatment of obesity.

The aim of this article is to focus on the fixed-dose combination of phentermine and topiramate, a new antiobesity drug recently approved by the US FDA. The mechanisms of weight loss for each drug in monotherapy is described, followed by the rationale for its use as a combination therapy and a comprehensive review of recently published clinical trials that assessed its efficacy and safety.

Safety assessment of combination therapies in the treatment of obesity: focus on naltrexone/bupropion extended release and phentermine-topiramate extended release

ABSTRACT Introduction: Few studies on combination therapies for the treatment of obesity had been conducted until recently, when two fixed-dose combinations, bupropion-naltrexone ER fixed-dose combination and phentermine-topiramate ER titrated-dose combinations were evaluated in clinical studies that ultimately led to FDA approval. Areas covered: In this review, we discuss safety concerns about both combinations, the rationale and history of combination therapies for obesity (including phentermine plus fenfluramine), and possible future new combinations. Expert opinion: Combination therapies are a promising new area in obesity treatment, similar to what occurs with diabetes and hypertension. Safety assessment is highly important due to the high number of potential users on a chronic basis.

Diabetes remission off medications is not a suitable endpoint for comparing bariatric/metabolic surgery with pharmacotherapy

To the Editor: In their publication inDiabetologia, Cummings et al [1] describe how they used a randomised trial to compare the best available intensive lifestyle and medical intervention (ILMI) against Roux-en-Y gastric bypass (RYGB), and concluded that surgery achieved greater type 2 diabetes remission in mildly to moderately obese patients. However, mean HbA1c values were not statistically different between groups at the end of study, which was not explicitly stated in the abstract. An OR for diabetes remission (defined as HbA1c <6.0% [<42.1 mmol/mol], off all diabetes medicines) of almost 20 looks quite impressive, but in our opinion this is not a suitable study endpoint for analysis. Given that the comparison group received intensive lifestyle with optimal medical intervention, and therefore the very point of the intervention was the use of medication, it seems inappropriate that a criterion of the primary endpoint of interest was whether or not the patient was off medication. It is well established that diabetes is a chronic disease and most patients are unable to control their diabetes with intensive lifestyle interventions (the same applies to obesity itself, despite being associated with greater and persistent stigma). Therefore, the discontinuation of several classes of medications for type 2 diabetes would give rise to disease deterioration. As expected with any other chronic disease, the control group could be well controlled, but, of course, on medication. Since a surgical procedure can be considered a chronic treatment for diabetes (because the anatomical changes are permanent), this seems to be an unfair comparison. We believe that a better judgment (which still would favour surgery in the great majority of cases) would be an HbA1c target that was independent of medication use. We acknowledge that the criteria for remission were not developed solely for this article and are being used in most bariatric/metabolic surgery studies, but because of the conclusion of the abstract and the absence of statistically significant differences in HbA1c at the end of the treatment, this comment seems appropriate at this point. Also of note is the conclusion about individuals with a BMI <35 kg/m. It is stated in the Results section that ‘In exploratory analyses, diabetes remission was not predicted by baseline BMI, age or sex, or by the amount of weight lost during 1 year, and there was no correlation between change in body weight and change in HbA1c at 6 or 12 months among those having RYGB; however, the study was not specifically powered to detect this.’ Furthermore, in the Discussion section the authors state that ‘there is still limited evidence from RCTs * Bruno Halpern brunohalpern@hotmail.com

Comment on Cummings and Cohen. Bariatric/Metabolic Surgery to Treat Type 2 Diabetes in Patients With a BMI <35 kg/m 2 . Diabetes Care 2016;39:924–933

In a recent article, Cummings and Cohen (1) compared glycemic outcomes after bariatric surgery in patients with BMI ≥35 or <35 kg/m2, concluding that there was no clear difference in outcomes between these BMI thresholds. To strengthen their argument, they discussed possible weight-independent effects of bariatric surgery on glycemic outcomes. Their article correctly recognized the 35 kg/m2 threshold used as an indication for bariatric surgery, based on a 1991 National Institutes of Health Consensus Statement (2), as arbitrary and probably not suitable for Asian patients, and it discussed the fact that initial BMI does not predict outcome in larger cohorts. However, many points discussed in the article should be analyzed with caution, given the limited number of less obese patients with long-term follow-up after metabolic surgery and the few existing comparisons of BMI extremes. Additionally, many studies have demonstrated that diabetes remission is associated with the amount of weight loss and that, …

Case Report of Acquired Generalized Lipodystrophy Associated With Common Variable Immunodeficiency

Context Acquired generalized lipodystrophy (AGL), a rare disorder characterized by loss of subcutaneous adipose tissue, is estimated to occur in association with autoimmune diseases in ~25% of the cases. Common variable immunodeficiency (CVI) is a condition known for its strong association with autoimmune diseases often occurring with negative autoantibodies. To the best of our knowledge, we describe the first known case of AGL in a patient with CVI. Case Description A 24-year-old man was referred to our center with hyperglycemia, hypertriglyceridemia, hepatomegaly, and a clear pattern of generalized fat loss. AGL had been diagnosed on the basis of the clinical and laboratory findings. Because of the presence of associated hypogammaglobulinemia, a diagnosis of CVI was subsequently established. Conclusions We propose that AGL be added to the list of possible diseases associated with CVI and, owing to the similar clinical presentation with type 1 diabetes mellitus, be included in the differential diagnosis of this condition, which is present in 1.5% of patients with CVI.

Medical Management of Obesity

The dramatic rise in the prevalence of obesity in the Western world over the last four decades (Global Strategy on Diet, Physical Activity and Health, WHO. http://www.who.int/dietphysicalactivity/strategy/eb11344/strategy_english_web.pdf. Accessed December 10, 2012) unfortunately has not been followed by effective measures for its long-term treatment, which still mainly relies on lifestyle modification through diet and exercise. Few medications are available for its treatment and surgical treatment, although growing considerably in the last decades, is only indicated for extreme obesity (BMI over 40 kg/m2) or in patients with considerable comorbidities.