Hermann Toplak

Management of Obesity in Adults: European Clinical Practice Guidelines

The development of consensus guidelines for obesity is complex. It involves recommending both treatment interventions and interventions related to screening and prevention. With so many publications and claims, and with the awareness that success for the individual is short-lived, many find it difficult to know what action is appropriate in the management of obesity. Furthermore, the significant variation in existing service provision both within countries as well as across the regions of Europe makes a standardised approach, even if evidence-based, difficult to implement. In formulating these guidelines, we have attempted to use an evidence-based approach while allowing flexibility for the practicing clinician in domains where evidence is currently lacking and ensuring that in treatment there is recognition of clinical judgment and of regional diversity as well as the necessity of an agreed approach by the individual and family. We conclude that i) physicians have a responsibility to recognise obesity as a disease and help obese patients with appropriate prevention and treatment, ii) treatment should be based on good clinical care and evidence-based interventions and iii) obesity treatment should focus on realistic goals and lifelong management.

Treatment modalities of obesity: what fits whom?

The prevalence of obesity is increasing in both developed and developing countries, with rates reaching ∼10–35% among adults in the Euro-American region. Obesity is associated with increased risks of cardiovascular diseases, type 2 diabetes, arthritis, and some type of cancers. Obesity significantly affects the quality of life and reduces the average life expectancy. The effective treatment of obesity should address both the medical and the social burden of this disease. Obesity needs to be treated within the health care system as any other complex disease, with empathy and without prejudice. Both health care providers and patients should know that the obesity treatment is a lifelong task. They should also set realistic goals before starting the treatment, whereas keeping in mind that even a modest weight loss of 5–15% significantly reduces obesity-related health risks. Essential treatment of obesity includes low-calorie low-fat diets, increased physical activity, and strategies contributing to the modification of lifestyle. Anti-obesity drugs facilitate weight loss and contribute to further amelioration of obesity-related health risks. A short-term weight loss, up to 6 months, is usually achieved easily. However, the long-term weight management is often associated with a lack of compliance, failures, and a high dropout rate. Regular physical activity, cognitive behavioral modification of lifestyle, and administration of anti-obesity drugs improve weight loss maintenance. Bariatric surgery is an effective strategy to treat severely obese patients. Bariatric surgery leads to a substantial improvement of comorbidities as well as to a reduction in overall mortality by 25–50% during the long-term follow-up. Obesity treatment should be individually tailored and the following factors should be taken into account: sex, the degree of obesity, individual health risks, psychobehavioral and metabolic characteristics, and the outcome of previous weight loss attempts. In the future, an evaluation of hormonal and genetic determinants of weight loss could also contribute to a better choice of individual therapy for a particular obese patient. A multilevel obesity management network of mutually collaborating facilities should be established to provide individually tailored treatment. Centers of excellence in obesity management represented by multidisciplinary teams should provide comprehensive programs for the treatment of obesity derived from evidence-based medicine.

Efficacy and tolerability of orlistat in the treatment of obesity : a 6-month dose-ranging study

AbstractObjective: To determine the weight-reducing efficacy of orlistat, a novel gastrointestinal lipase inhibitor, and to define the optimal dosage regimen and establish the tolerability of the drug when used for a 6-month treatment period. Methods: The study was a multicentre randomised, double-blind, parallel group in design and involved 676 obese male and female subjects aged at least 18 years with a body mass index between 28 and 43 kg · m−2. Following a 5-week placebo run-in period, subjects were randomised to receive orlistat 30 mg, 60 mg, 120 mg, 240 mg or matching placebo three times a day (tid) for 24 weeks during meals. Patients were maintained on a mildly hypocaloric diet throughout the study period. The primary efficacy parameter was body weight change over time. Results: Orlistat resulted in a significantly greater mean loss of body weight than observed in the placebo group. In absolute terms, mean weight loss was greatest in the 120 mg group (9.8%). More orlistat- than placebo-treated patients lost >10% of initial body weight (37% of the 120 mg group vs 19% of the placebo group). Orlistat was well tolerated. Predictably, in view of its known pharmacological effects, more orlistat-treated patients experienced gastrointestinal events. Mean levels of vitamins A, D and E, and β-carotene remained within the clinical reference ranges in all treatment groups and rarely required supplementation. After 24 weeks, plasma concentrations of orlistat were either non-measurable or detected at the assays limit of quantitation. Conclusion: Orlistat treatment results in a dose-dependent reduction in body weight in obese subjects and is well tolerated. Orlistat 120 mg tid represents the optimal dosage regimen.

Prevalence, Pathophysiology, Health Consequences and Treatment Options of Obesity in the Elderly: A Guideline

The prevalence of obesity is rising progressively, even among older age groups. By the year 2030–2035 over 20% of the adult US population and over 25% of the Europeans will be aged 65 years and older. The predicted prevalence of obesity in Americans, 60 years and older was 37% in 2010. The predicted prevalence of obesity in Europe in 2015 varies between 20 and 30% dependent on the model used. This means 20.9 million obese 60+ people in the USA in 2010 and 32 million obese elders in 2015 in the EU. Although cut-off values of BMI, waist circumference and percentages of fat mass have not been defined for the elderly (nor for the elderly of different ethnicity), it is clear from several meta-analyses that mortality and morbidity associated with overweight and obesity only increases at a BMI above 30 kg/m2. Thus, treatment should only be offered to patients who are obese rather than overweight and who also have functional impairments, metabolic complications or obesity-related diseases, that can benefit from weight loss. The weight loss therapy should aim to minimize muscle and bone loss but also vigilance as regards the development of sarcopenic obesity – a combination of an unhealthy excess of body fat with a detrimental loss of muscle and fat-free mass including bone – is important in the elderly, who are vulnerable to this outcome. Life-style intervention should be the first step and consists of a diet with a 500 kcal (2.1 MJ) energy deficit and an adequate intake of protein of high biological quality together with calcium and vitamin D, behavioural therapy and multi-component exercise. Multi-component exercise includes flexibility training, balance training, aerobic exercise and resistance training. The adherence rate in most studies is around 75%. Knowledge of constraints and modulators of physical inactivity should be of help to engage the elderly in physical activity. The role of pharmacotherapy and bariatric surgery in the elderly is largely unknown as in most studies people aged 65 years and older have been excluded.

European Guidelines for Obesity Management in Adults

Obesity is a chronic metabolic disease characterised by an increase of body fat stores. It is a gateway to ill health, and it has become one of the leading causes of disability and death, affecting not only adults but also children and adolescents worldwide. In clinical practice, the body fatness is estimated by BMI, and the accumulation of intra-abdominal fat (marker for higher metabolic and cardiovascular disease risk) can be assessed by waist circumference. Complex interactions between biological, behavioural, social and environmental factors are involved in regulation of energy balance and fat stores. A comprehensive history, physical examination and laboratory assessment relevant to the patients obesity should be obtained. Appropriate goals of weight management emphasise realistic weight loss to achieve a reduction in health risks and should include promotion of weight loss, maintenance and prevention of weight regain. Management of co-morbidities and improving quality of life of obese patients are also included in treatment aims. Balanced hypocaloric diets result in clinically meaningful weight loss regardless of which macronutrients they emphasise. Aerobic training is the optimal mode of exercise for reducing fat mass while a programme including resistance training is needed for increasing lean mass in middle-aged and overweight/obese individuals. Cognitive behavioural therapy directly addresses behaviours that require change for successful weight loss and weight loss maintenance. Pharmacotherapy can help patients to maintain compliance and ameliorate obesity-related health risks. Surgery is the most effective treatment for morbid obesity in terms of long-term weight loss. A comprehensive obesity management can only be accomplished by a multidisciplinary obesity management team. We conclude that physicians have a responsibility to recognise obesity as a disease and help obese patients with appropriate prevention and treatment. Treatment should be based on good clinical care, and evidence-based interventions; should focus on realistic goals and lifelong multidisciplinary management.

Exposure To Elevated D-Glucose Concentrations Modulates Vascular Endothelial Cell Vasodilatory Response

The possible role of endothelial dysfunction in early stages of uncomplicated diabetes mellitus was investigated in porcine aortic endothelial cells. Prolonged exposure to various D-glucose concentrations resulted in concentration-dependent amplification of agonist-induced Ca2+ mobilization, whereas L-glucose and D-mannitol failed to mimic the effect of D-glucose. This stimulatory effect of high D-glucose on endothelial Ca2+ mobilization could be antagonized by coincubation with cytochalasin B, which prevented D-glucose uptake into the cells. In agreement with its effect on agonist-induced Ca2+ response, prolonged preincubation with pathological D-glucose concentrations amplified formation of endothelium-derived relaxing factor, which is well established to be strictly attributable to increases in endothelial free Ca2+. In contrast to endothelium-derived relaxing factor formation stimulated by receptor-interacting autacoids, preincubation with high D-glucose failed to modulate A 23,187-induced endothelium-derived relaxing factor formation, which is attributable to unphysiological increases in endothelial free Ca2+ by this ionophore. Similar to its effect on D-glucose-mediated amplification of agonist-stimulated Ca2+ mobilization, cytochalasin B abolished the stimulatory effect of high D-glucose on endothelium-derived relaxing factor formation. We therefore suggest that prolonged exposure to pathological high D-glucose concentrations results in an enhanced endothelium-derived relaxing factor formation caused by amplification of agonist-stimulated Ca2+ mobilization in endothelial cells. This mechanism may be of particular importance representing a possible basis of pathological vasodilation and reduced peripheral resistance in early stages of diabetes mellitus.

Prevention of Type 2 Diabetes in Subjects With Prediabetes and Metabolic Syndrome Treated With Phentermine and Topiramate Extended Release

OBJECTIVE To evaluate over 108 weeks the effect of phentermine and topiramate extended release (PHEN/TPM ER) treatment on progression to type 2 diabetes and/or cardiometabolic disease in subjects with prediabetes and/or metabolic syndrome (MetS) at baseline. RESEARCH DESIGN AND METHODS Subanalysis of a phase 3, randomized, placebo-controlled, double-blind study of overweight/obese subjects (BMI ≥27 to ≤45 kg/m2) with two or more comorbidities. Subjects were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg (7.5/46), or PHEN 15 mg/TPM ER 92 mg (15/92) plus lifestyle modifications for 108 weeks. Percent weight loss in the intent-to-treat population using multiple imputation (ITT-MI), annualized incidence rate of progression to type 2 diabetes, and changes in glycemia, lipid parameters, blood pressure, and waist circumference were evaluated. RESULTS At baseline, 475 subjects met the criteria for prediabetes and/or MetS. After 108 weeks, subjects with prediabetes and/or MetS in the placebo, 7.5/46, and 15/92 groups experienced mean percent weight loss of 2.5, 10.9, and 12.1%, respectively (ITT-MI; P < 0.0001 vs. placebo), associated with reductions of 70.5 and 78.7% in the annualized incidence rate of type 2 diabetes for those receiving 7.5/46 and 15/92, respectively (ITT, P < 0.05), versus placebo. The ability of PHEN/TPM ER to prevent diabetes was related to degree of weight lost and was accompanied by significant improvements in cardiometabolic parameters. PHEN/TPM ER was well tolerated by this subgroup over 2 years. CONCLUSIONS PHEN/TPM ER plus lifestyle modification produced significant weight loss and markedly reduced progression to type 2 diabetes in overweight/obese patients with prediabetes and/or MetS, accompanied by improvements in multiple cardiometabolic disease risk factors.

Evaluation of a new DNA test compared with the lactose hydrogen breath test for the diagnosis of lactase non-persistence.

Background and aims Recent publications have found that the CC genotype of the DNA variant −13910 T/C upstream of the LCT gene is associated with lactase non-persistence. We therefore compared the value of DNA testing for this variant (DNA test) with the lactose hydrogen breath test (H2 test), which is the clinical standard for the diagnosis of lactase non-persistence. Patients and methods One hundred and twenty-three consecutive patients with suspected lactose malabsorption were tested for the presence of the −13910 T/C variant by polymerase chain reaction-restriction fragment length polymorphism analysis. These patients also underwent the H2 test after ingestion of 50 g lactose. Results Thirty-seven subjects had a CC genotype of the −13910 T>C polymorphism suggesting lactase non-persistence; 36 (97%) had also a positive H2 test. Eighty-six subjects had either a TC or a TT genotype suggestive of lactase persistence. Seventy-four (86%) of these tested negative on the H2 test, while 12 patients had a positive H2 test. In eight of these 12 patients duodenal biopsies showed no evidence of small bowel disease. One patient carrying a CC genotype had a negative H2 test. In this patient the rise in serum glucose after oral lactose was normal, furthermore H2 non-excretion was also excluded. Conclusions An excellent correlation is observed between a CC genotype and a positive H2 test, whereas the correlation between a TC or TT genotype and a negative H2 test result is less strong. Analysis of the −13910 T/C variant can be considered a good test for predicting the presence of lactase non-persistence in a patient population with suspected lactose malabsorption.

Aldosterone and parathyroid hormone interactions as mediators of metabolic and cardiovascular disease

Inappropriate aldosterone and parathyroid hormone (PTH) secretion is strongly linked with development and progression of cardiovascular (CV) disease. Accumulating evidence suggests a bidirectional interplay between parathyroid hormone and aldosterone. This interaction may lead to a disproportionally increased risk of CV damage, metabolic and bone diseases. This review focuses on mechanisms underlying the mutual interplay between aldosterone and PTH as well as their potential impact on CV, metabolic and bone health. PTH stimulates aldosterone secretion by increasing the calcium concentration in the cells of the adrenal zona glomerulosa as a result of binding to the PTH/PTH-rP receptor and indirectly by potentiating angiotensin 2 induced effects. This may explain why after parathyroidectomy lower aldosterone levels are seen in parallel with improved cardiovascular outcomes. Aldosterone mediated effects are inappropriately pronounced in conditions such as chronic heart failure, excess dietary salt intake (relative aldosterone excess) and primary aldosteronism. PTH is increased as a result of (1) the MR (mineralocorticoid receptor) mediated calciuretic and magnesiuretic effects with a trend of hypocalcemia and hypomagnesemia; the resulting secondary hyperparathyroidism causes myocardial fibrosis and disturbed bone metabolism; and (2) direct effects of aldosterone on parathyroid cells via binding to the MR. This adverse sequence is interrupted by mineralocorticoid receptor blockade and adrenalectomy. Hyperaldosteronism due to klotho deficiency results in vascular calcification, which can be mitigated by spironolactone treatment. In view of the documented reciprocal interaction between aldosterone and PTH as well as the potentially ensuing target organ damage, studies are needed to evaluate diagnostic and therapeutic strategies to address this increasingly recognized pathophysiological phenomenon.

Effects of low-dose L-arginine on insulin-mediated vasodilatation and insulin sensitivity

The present study was carried out to evaluate the effect of a low‐dose intravenous supplementation of l‐arginine on insulin‐mediated vasodilatation and insulin sensitivity. The study was performed in healthy subjects (n = 7) and patients with obesity (n = 9) and non‐insulin‐dependent diabetes mellitus (NIDDM) (n = 9). Insulin‐mediated vasodilatation was measured by venous occlusion plethysmography during the insulin suppression test, evaluating insulin sensitivity. Experiments were performed twice in each subject in the presence or absence of a concomitant infusion of l‐arginine (0.52 mg kg−1 min−1). l‐Arginine restored the impaired insulin‐mediated vasodilatation observed in obesity (22.4 ± 4.1%, P < 0.01 vs. without l‐arginine) and NIDDM (20.3 ± 3.2%, P < 0.01 vs. without l‐arginine). In healthy subjects, no effect on insulin mediated‐vasodilatation was observed (24.8 ± 3.1% vs. 21.4 ± 3.1%). Insulin sensitivity was improved significantly (P < 0.001) in all three groups by infusion of l‐arginine. No effect of l‐arginine was observed on insulin, insulin‐like growth factor I (IGF‐I), free fatty acids (FFAs) or C‐peptide levels during the insulin suppression test. Our data indicate that defective insulin‐mediated vasodilatation in obesity and NIDDM can be normalized by intravenous l‐arginine. Furthermore, l‐arginine improves insulin sensitivity in obese patients and NIDDM patients as well as in healthy subjects, indicating a possible mechanism that is different from the restoration of insulin‐mediated vasodilatation.