Weight loss interventions and nonalcoholic fatty liver disease: Optimizing liver outcomes.

The growth in prevalence of obesity, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) has become one of the most important global health challenges. The three chronic diseases are closely linked in their epidemiology and pathophysiology. Currently, weight loss is the most effective treatment for NAFLD (even in the minority of patients with NAFLD who do not have obesity) and is recommended in all national and international guidelines. Accumulating evidence has shown that weight loss, whether achieved by diet and lifestyle interventions, bariatric surgery or pharmacotherapy, can improve biomarkers of NAFLD, as well as prevent progression and, in some cases, reverse fibrosis. There is a dose dependency of weight loss with NAFLD improvement. Pharmacotherapy with antiobesity medications, alone or in combination with intensive lifestyle interventions or other weight-loss drugs, is closing the efficacy gap between diet and exercise and weight-loss surgery in efficacy at reversing obesity. Given the importance of providing effective weight-loss treatment to patients with NAFLD, weight management services need to be made increasingly available and embedded within hepatology services. This narrative review addresses the evidence that weight loss optimizes liver outcomes in people with NAFLD.

Effectiveness and cost-effectiveness of interventions that cause weight loss and reduce the risk of cardiovascular disease.

BACKGROUND: Overweight/obesity is associated with significant morbidity, mortality and costs. Weight loss has been shown to reverse some of these effects, reducing the risk of chronic diseases such as cardiovascular disease (CVD). AIM: To determine the potential monies available, from an English National Health Service perspective, for weight loss interventions to be cost-effective in the prevention of CVD. METHODS: A Markov model was developed, populated with overweight/obese individuals from the Health Survey for England, aged 30-74 years, free of pre-existing CVD and with available risk factor information to calculate CVD risk. All individuals were free of CVD at baseline and, with each annual cycle, could transition to other health states of primary CVD, secondary CVD or death according to transition probabilities for a maximum period of 10 years, or until death. Utilities, costs and the effects of weight loss on CVD risk factors were applied. The potential monies available for CVD prevention strategies, provided the incremental cost-effectiveness ratio met UK arbitrary limits of between £20 000 and £30 000, was determined. RESULTS: Applying the effects of weight loss on CVD risk factors prevented 4 CVD events and saved 17 quality-adjusted life-years over 10 years per 1000 individuals. £34 to £51 was available per person per year for up to 10 years when meeting the UK arbitrary limits. CONCLUSIONS: Individual annual financial allowances for weight loss interventions to be considered cost-effective is relatively low; however, as a large proportion of the population is affected, wide cheap societal interventions are important.

Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects.

BACKGROUND: The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established. METHODS: We enrolled in our study 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both to assess the cardiovascular consequences of weight management with and without sibutramine in subjects at high risk for cardiovascular events. All the subjects received sibutramine in addition to participating in a weight-management program during a 6-week, single-blind, lead-in period, after which 9804 subjects underwent random assignment in a double-blind fashion to sibutramine (4906 subjects) or placebo (4898 subjects). The primary end point was the time from randomization to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death). RESULTS: The mean duration of treatment was 3.4 years. The mean weight loss during the lead-in period was 2.6 kg; after randomization, the subjects in the sibutramine group achieved and maintained further weight reduction (mean, 1.7 kg). The mean blood pressure decreased in both groups, with greater reductions in the placebo group than in the sibutramine group (mean difference, 1.2/1.4 mm Hg). The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.31; P=0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; P=0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; P=0.03). The rates of cardiovascular death and death from any cause were not increased. CONCLUSIONS: Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause. (Funded by Abbott; ClinicalTrials.gov number, NCT00234832.)

Prevalence of Baseline Cardiac Arrhythmias in Participants with Overweight or Obesity in Phase 1 Clinical Trials: Analysis of 24-Hour Holter Electrocardiogram Recordings.

Although estimates of the prevalence of cardiac arrhythmias in healthy volunteers exist, there is a lack of baseline data in other specific populations, such as people living with overweight and obesity, who are increasingly involved in clinical trials. This study investigated the baseline prevalence of arrhythmias in participants with overweight or obesity in 2 phase 1 trials of weight management medications (NCT03661879, NCT03308721). Participants aged 18-55 years, without a history of cardiovascular disease, and with body mass index (BMI) of 25.0-39.9 kg/m2 , were screened for abnormalities in vital signs, electrocardiogram (ECG) recordings, and electrolytes. Baseline 24-hour ECG (Holter) data were collected and manually reviewed by a cardiologist. The primary endpoint was the proportion of participants with ≥1 episode of the predefined cardiac arrhythmias. Continuous 12-lead ECG data were obtained from 207 participants. Most arrhythmias occurred in <3% of participants. Atrioventricular blocks and other potentially malignant arrhythmias were uncommon. There were no associations with age, sex, or BMI. Prevalence of atrioventricular blocks, nonsustained ventricular tachycardia, and other potentially malignant arrhythmias mirrored those reported in healthy participants with normal weight. In clinical trials of weight management medication, knowledge of the baseline prevalence of arrhythmias in people with overweight and obesity may inform trial eligibility criteria, improve on-trial decisions, and could be useful in discussions with health authorities. Baseline Holter readings and real-time ECG telemetry monitoring should be considered in such trials if arrhythmia risk is intrinsic to the molecule, or when signals have been observed in preclinical studies.

Future directions in obesity pharmacotherapy.

There is a growing unmet need for more effective treatment of obesity and its complications. While current anti-obesity medications are effective and offer real clinical benefits over diet and lifestyle interventions, they cannot meet the levels of efficacy and reduction of hard endpoint outcomes seen with bariatric surgery. As knowledge on the control of body weight unravels, the complexity of this physiology opens the opportunity to new druggable targets. Currently, gut peptide analogues such as semaglutide, a glucagon like peptide-1 (GLP-1) receptor agonist, and the dual agonist GLP-1 and gastric inhibitory polypeptide (GIP) tirzepatide are the furthest advanced in clinical development and seem likely to meet current regulatory requirements within the next year or so. However, current regulatory requirements are out of step with the efficacy of new compounds and concepts relating to obesity and its complications. Many other drugs in early development will target different pathways of energy balance, raising the possibility of drug combinations to maximise efficacy as for other chronic disease such as hypertension and diabetes. This will allow more complex and personalised guidelines to evolve.

Body mass index trajectories among people with obesity and association with mortality: Evidence from a large Israeli database.

OBJECTIVE: Previous studies using longitudinal weight data to characterize obesity are based on populations of limited size and mostly include individuals of all body mass index (BMI) levels, without focusing on weight changes among people with obesity. This study aimed to identify BMI trajectories over 5 years in a large population with obesity, and to determine the trajectories' association with mortality. METHODS: For inclusion, individuals aged 30-74 years at index date (1 January 2013) with continuous membership in Clalit Health Services from 2008 to 2012 were required to have ≥1 BMI measurement per year in ≥3 calendar years during this period, of which at least one was ≥30 kg/m2. Latent class analysis was used to generate BMI trajectories over 5 years (2008-2012). Cox proportional hazards models were used to assess the association between BMI trajectories and all-cause mortality during follow-up (2013-2017). RESULTS: In total, 367,141 individuals met all inclusion criteria. Mean age was 57.2 years; 41% were men. The optimal model was a quadratic model with four classes of BMI clusters. Most individuals (90.0%) had stable high BMI over time. Individuals in this cluster had significantly lower mortality than individuals in the other trajectory clusters (p < 0.01), including clusters of people with dynamic weight trajectories. CONCLUSIONS: The results of the current study show that people with stable high weight had the lowest mortality of all four BMI trajectories identified. These findings help to expand the scientific understanding of the impact that weight trajectories have on health outcomes, while demonstrating the challenges of discerning the cumulative effects of obesity and weight change, and suggest that dynamic historical measures of BMI should be considered when assessing patients' future risk of obesity-related morbidity and mortality, and when choosing a treatment strategy.

The weight lowering effect of sibutramine and its impact on serum lipids in cardiovascular high risk patients with and without type 2 diabetes mellitus - an analysis from the SCOUT lead-in period.

BACKGROUND: Obesity, type 2 diabetes mellitus (T2D) and unhealthy blood lipid profile are strongly associated with the risk of developing cardiovascular disease (CVD). We examined whether blood lipid changes with short term administration of the weight lowering drug, sibutramine and lifestyle modification in obese and overweight high-risk patients was associated with T2D status at screening. METHODS: The Sibutramine Cardiovascular OUTcomes (SCOUT) trial included obese and overweight patients at increased risk of cardiovascular events. All patients received guidance on diet and exercise plus once-daily 10 mg sibutramine during the 6-week, single blind lead-in period. Multivariable regression models were used to investigate factors associated with changes in lipid levels during the first four weeks of treatment. RESULTS: A total of 10 742 patients received at least one dose of sibutramine during the 6-week lead-in period of SCOUT. After four weeks, patients experienced mean reductions in low density lipoprotein (LDL-C) 0.19 mmol/L, high density lipoprotein (HDL-C) 0.019 mmol/L, very low density lipoprotein (VLDL-C) 0.08 mmol/L, total cholesterol (TC) 0.31 mmol/L and triglycerides 0.24 mmol/L (p < 0.0001 for each). Four week changes in LDL-C, HDL-C and total cholesterol for patients without vs. with T2D were: LDL-C:-0.25 mmol/L vs. -0.18 mmol/L, P = 0.0004; HDL-C: -0.03 mmol/L vs. -0.02 mmol/L, P = 0.0014; total cholesterol: -0.37 mmol/l vs. -0.29 mmol/l, P = 0.0009. Multivariable regression analysis showed that similar decreases in body mass index (BMI) affected lipid changes differently according to diabetes status. A 1 kg/m2 decrease in BMI in patients with T2D was associated with -0.09 mmol/L in LDL-C (P < 0.0001) and -0.01 mmol/L in HDL-C (P = 0.0001) but larger changes of -0.16 mmol/L LDL-C and -0.03 mmol/L in HDL-C (P < 0.0001 for both) in patients without T2D. CONCLUSION: Short term weight management with sibutramine therapy in obese or overweight high-risk patients induced significant mean reductions for all lipids. Those without T2D benefited most. Patients with hyperlipidaemia and the less obese patients also had greater falls in LDL-C and TC during weight loss. The trial is registered at ClinicalTrial.gov number: NCT00234832.

A comprehensive descriptive assessment of obesity related chronic morbidity and estimated annual cost burden from a population-based electronic health record database.

BACKGROUND: The growing prevalence of obesity and its complications pose a huge burden on the individual and health care systems worldwide. This study presents the frequency of multiple prevalent co-morbidities and estimated annual cost burden by body mass index (BMI) groups, age, and sex among the Israeli adult population to provide policy makers with further evidence to appropriately target interventions. METHODS: This cross-sectional study utilized population-based electronic medical records from the largest payer-provider health fund in Israel. The population included individuals ≥25 years as of 01/01/2014. A new approach assessing body system-related morbidity (BSRM) prevalence was assessed along with estimated annual cost burden for the year 2015 and presented across BMI group, age, and sex via heat maps. RESULTS: Among 1,756,791 adults, 65% had an elevated BMI (BMI > 25 kg/m2). Heat map analysis demonstrated a higher multi-BSRM prevalence and relative estimated annual cost burden among participants with obesity in all age groups. There was a notably higher multi-BSRM prevalence among men and women aged 25-29 with class III obesity (26 and 30%, respectively) compared to the corresponding BMI groups between 18·5- < 25 kg/m2 (5 and 9%, respectively). Healthcare costs were 1·72 times higher among men aged 25-29 with class III obesity and 2·75 times among women aged 25-29 with class III obesity compared to those of healthy weight. CONCLUSIONS: The detailed analysis describes the uneven distribution of burdens across BMI groups, age, and sex allowing policy makers to identify sub-populations for targeted interventions.

Association between fat mass through adolescence and arterial stiffness: a population-based study from The Avon Longitudinal Study of Parents and Children.

BACKGROUND: The link between adiposity, metabolic abnormalities, and arterial disease progression in children and adolescents remains poorly defined. We aimed to assess whether persistent high adiposity levels are associated with increased arterial stiffness in adolescence and any mediation effects by common metabolic risk factors. METHODS: We included participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had detailed adiposity measurements between the ages 9-17 years and arterial stiffness (carotid to femoral pulse wave velocity [PWV]) measured at age 17 years. Body-mass index (BMI) and waist-to-height ratio were calculated from weight, height, and waist circumference measurements whereas fat mass was assessed using repeated dual-energy x-ray absorptiometry (DEXA) scans. We used total and trunk fat mass indices (FMIs) to classify participants as normal (<75th percentile) or high (>75th percentile) FMI. We classified participants as being metabolically unhealthy if they had three or more of the following risk factors: high levels of systolic blood pressure, triglycerides, or glucose (all >75th percentile) or low levels of high-density lipoprotein (<25th percentile). We used multivariable linear regression analysis to assess the relationship between PWV and exposure to adiposity, and tested for linear trend of PVW levels across ordinal groups. We used latent class growth mixture modelling analysis to assess the effect of longitudinal changes in adiposity indices through adolescence on arterial stiffness. FINDINGS: We studied 3423 participants (1866 [54·5%] female and 1557 [45·5%] male). Total fat mass was positively associated with PWV at age 17 years (0·004 m/s per kg, 95% CI 0·001-0·006; p=0·0081). Persistently high total FMI and trunk FMI between ages 9 and 17 years were related to greater PWV (0·15 m/s per kg/m2, 0·05-0·24; p=0·0044 and 0·15 m/s per kg/m2, 0·06-0·25; p=0·0021) compared with lower FMI. Metabolic abnormalities amplified the adverse effect of high total FMI on arterial stiffness (PWV 6·0 m/s [95% CI 5·9-6·0] for metabolically healthy participants and 6·2 m/s [5·9-6·4] for metabolically unhealthy participants). Participants who restored normal total FMI in adolescence (PWV 5·8 m/s [5·7-5·9] for metabolically healthy and 5·9 m/s [5·6-6·1] for metabolically unhealthy) had comparable PWV to those who had normal FMI throughout (5·7 m/s [5·7-5·8] for metabolically healthy and 5·9 m/s [5·8-5·9] for metabolically unhealthy). INTERPRETATION: Persistently high fat mass during adolescence was associated with greater arterial stiffness and was further aggravated by an unfavourable metabolic profile. Reverting to normal FMI in adolescence was associated with normal PWV, suggesting adolescence as an important period for interventions to tackle obesity in the young to maximise long-term vascular health. FUNDING: UK Medical Research Council, Wellcome Trust, British Heart Foundation, and AFA Insurances.

Tolerability of sibutramine during a 6-week treatment period in high-risk patients with cardiovascular disease and/or diabetes: a preliminary analysis of the Sibutramine Cardiovascular Outcomes (SCOUT) Trial.

Uncertainties about the cardiovascular safety of sibutramine led to the SCOUT trial that is investigating sibutramine plus weight management in high-risk, overweight/obese patients. A 6-week lead-in period during which all patients received sibutramine permitted an initial assessment of tolerability. A total of 10,742 patients received sibutramine and 3.1% of these discontinued due to an adverse event; issues affecting more than 10 patients were drug intolerance, headache, insomnia, nausea, dry mouth, and constipation-, tachycardia-, and hypertension-related events. Serious adverse events, most commonly associated with the System Organ Class, Cardiac disorders, were reported by 2.7% of patients; however, the majority was not considered sibutramine-related. Adverse events relating to high blood pressure and/or pulse rate, whether reported as adverse events leading to discontinuation, or serious adverse events were reported by less than 0.2% of patients. No serious or individual events leading to discontinuation occurred in more than 25 patients. There were 15 (0.1%) deaths; 10 were attributed to a cardiovascular cause. Discontinuations for adverse events were lower than anticipated. Serious adverse events generally reflected sibutramine's known pharmacology or were related to cardiac disorders already present in this high-risk population. When compared with epidemiological data, overall mortality rate was low and sibutramine was well tolerated in this mainly off-label population. No new safety issues were detected.

Engaging patients, clinicians and health funders in weight management: the Counterweight Programme.

BACKGROUND: The Counterweight Programme provides an evidence based and effective approach for weight management in routine primary care. Uptake of the programme has been variable for practices and patients. Aim. To explore key barriers and facilitators of practice and patient engagement in the Counterweight Programme and to describe key strategies used to address barriers in the wider implementation of this weight management programme in UK primary care. METHODS: All seven weight management advisers participated in a focus group. In-depth interviews were conducted with purposeful samples of GPs (n = 7) and practice nurses (n = 15) from 11 practices out of the 65 participating in the programme. A total of 37 patients participated through a mixture of in-depth interviews (n = 18) and three focus groups. Interviews and focus groups were analysed for key themes that emerged. RESULTS: Engagement of practice staff was influenced by clinicians' beliefs and attitudes, factors relating to the way the programme was initiated and implemented, the programme content and organizational/contextual factors. Patient engagement was influenced by practice endorsement of the programme, clear understanding of programme goals, structured proactive follow-up and perception of positive outcomes. CONCLUSIONS: Having a clear understanding of programme goals and expectations, enhancing self-efficacy in weight management and providing proactive follow-up is important for engaging both practices and patients. The widespread integration of weight management programmes into routine primary care is likely to require supportive public policy.

The effects of Ramadan fasting on activity and energy expenditure.

Background: Fasting during the month of Ramadan entails abstinence from eating and drinking between dawn and sunset and a major shift in meal times and patterns with associated changes in several hormones and circadian rhythms; whether there are accompanying changes in energy metabolism is unclear. Objective: We have investigated the impact of Ramadan fasting on resting metabolic rate (RMR), activity, and total energy expenditure (TEE). Design: Healthy nonobese volunteers (n = 29; 16 women) fasting during Ramadan were recruited. RMR was measured with the use of indirect calorimetry. In subgroups of participants, activity (n = 11; 5 women) and TEE (n = 10; 5 women) in free-living conditions were measured with the use of accelerometers and the doubly labeled water technique, respectively. Body composition was measured with the use of bioelectrical impedance. Measurements were repeated after a wash-out period of between 1 and 2 mo after Ramadan. Nonparametric tests were used for comparative statistics. Results: Ramadan fasting did not result in any change in RMR (mean ± SD: 1365.7 ± 230.2 compared with 1362.9 ± 273.6 kcal/d for Ramadan and post-Ramadan respectively, P = 0.713, n = 29). However, controlling for the effects of age, sex, and body weight, RMR was higher in the first week of Ramadan than in subsequent weeks. During Ramadan, the total number of steps walked were significantly lower (n = 11, P = 0.001), while overall sleeping time was reduced and different sleeping patterns were seen. TEE did not differ significantly between Ramadan and post-Ramadan (mean ± SD: 2224.1 ± 433.7 compared with 2121.0 ± 718.5 kcal/d for Ramadan and post-Ramadan, P = 0.7695, n = 10). Conclusions: Ramadan fasting is associated with reduced activity and sleeping time, but no significant change in RMR or TEE. Reported weight changes with Ramadan in other studies are more likely to be due to differences in food intake. This trial is registered at clinicaltrials.gov as NCT02696421.

Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA.

Fatty acid metabolism in the hypothalamus has recently been shown to regulate feeding. The selective estrogen receptor modulator tamoxifen (TMX) exerts a potent anorectic effect. Here, we show that the anorectic effect of TMX is associated with the accumulation of malonyl-CoA in the hypothalamus and inhibition of fatty acid synthase (FAS) expression specifically in the ventromedial nucleus of the hypothalamus (VMN). Furthermore, we demonstrate that FAS mRNA expression is physiologically regulated by fasting and refeeding in the VMN but not in other hypothalamic nuclei. Thus, the VMN appears to be the hypothalamic site where regulation of FAS and feeding converge. Supporting the potential clinical relevance of these observations, reanalysis of a primary breast cancer prevention study showed that obese women treated with TMX gained significantly less body weight over a 6-year period than obese women given placebo. The finding that TMX can modulate appetite through alterations in FAS expression and malonyl-CoA levels suggests a link between hypothalamic sex steroid receptors, fatty acid metabolism, and feeding behavior.

Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study.

BACKGROUND: Rimonabant, a selective cannabinoid type 1 receptor blocker, reduces bodyweight and improves cardiovascular and metabolic risk factors in non-diabetic overweight or obese patients. The aim of the RIO-Diabetes trial was to assess the efficacy and safety of rimonabant in overweight or obese patients with type 2 diabetes that was inadequately controlled by metformin or sulphonylureas. METHODS: 1047 overweight or obese type 2 diabetes patients (body-mass index 27-40 kg/m2) with a haemoglobin A1c (HbA1c) concentration of 6.5-10.0% (mean 7.3% [SD 0.9] at baseline) already on metformin or sulphonylurea monotherapy were given a mild hypocaloric diet and advice for increased physical activity, and randomly assigned placebo (n=348), 5 mg/day rimonabant (360) or 20 mg/day rimonabant (339) for 1 year. Two individuals in the 5 mg/day group did not receive double-blind treatment and were thus not included in the final analysis. The primary endpoint was weight change from baseline after 1 year of treatment. Analyses were done on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov, number NCT00029848. FINDINGS: 692 patients completed the 1 year follow-up; numbers in each group after 1 year were much the same. Weight loss was significantly greater after 1 year in both rimonabant groups than in the placebo group (placebo: -1.4 kg [SD 3.6]; 5 mg/day: -2.3 kg [4.2], p=0.01 vs placebo; 20 mg/day: -5.3 kg [5.2], p<0.0001 vs placebo). Rimonabant was generally well tolerated. The incidence of adverse events that led to discontinuation was slightly greater in the 20 mg/day rimonabant group, mainly due to depressed mood disorders, nausea, and dizziness. INTERPRETATION: These data indicate that 20 mg/day rimonabant, in combination with diet and exercise, can produce a clinically meaningful reduction in bodyweight and improve HbA1c and a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas.

The comparative effects of bariatric surgery on weight and type 2 diabetes.

BACKGROUND: Epidemiological evidence confirms that risk of developing type 2 diabetes is related to weight gain. Weight reduction is beneficial as relative risk is reduced to 0.13 for weight loss >20 kg. This raises the question of effectiveness of bariatric surgery on 1) weight loss and 2) diabetes-related outcomes in morbidly obese patients. METHODS: We reviewed the literature using Medline. Only 2 meta-analyses reporting on both outcomes were included, as well as 50 systematic reviews or primary studies. RESULTS: Meta-analyses mainly based on case series data as well as controlled studies confirm that bariatric surgery is highly effective in obtaining weight reduction in morbidly obese patients up to 60% of the excess weight, along with resolution of preoperative diabetes in more than 75% of cases. Among bariatric surgery techniques, malabsorptive procedures (biliopancreatic diversion and gastric bypass) appear to be more effective on both outcomes than restrictive procedures (gastroplasty and gastric banding). CONCLUSION: Even if more studies are needed to confirm current evidence, bariatric surgery is effective for controlling diabetes. It appears as an efficient strategy from economic modeling due to savings from reduction in diabetes-related costs.

Growth hormone (GH) replacement therapy in GH deficient adults: predictors of one-year metabolic and clinical response.

OBJECTIVE: This study investigated whether baseline status could predict the responsiveness to one-year growth hormone (GH) replacement therapy in adult GH deficient (GHD) patients. DESIGN: A total of 380 European patients with adult onset GHD due to non-functioning pituitary adenoma that had been enrolled in Pfizer International Metabolic Database (KIMS), and that had completed one year of GH replacement therapy within KIMS, were studied. RESULTS: The mean initial dose of GH was 0.22 (SEM 0.01) mg/day and after one year, the mean dose was 0.36 (0.01) mg/day. The mean insulin-like growth factor-I (IGF-I) SD score increased from -1.75 (0.08) at baseline to 0.47 (0.05) after one year. Quality of life (QoL)-Assessment of GHD in Adults (QoL-AGHDA), waist circumference, waist:hip ratio, and serum lipid pattern improved. Women received a higher dose of GH than men after one year, and demonstrated similar treatment response. In multiple stepwise forward regression analyses, the one-year changes in QoL-AGHDA score, waist:hip ratio, and serum low density lipoprotein-cholesterol (LDL-C) level correlated inversely with the baseline values of the same variable. In addition, the change after one year in QoL-AGHDA score correlated inversely with duration of hypopituitarism and baseline serum high density lipoprotein-cholesterol (HDL-C) level, and the change in waist:hip ratio correlated inversely, although more weakly, with baseline serum HDL-C level and UK citizenship and positively with baseline waist circumference and the initial GH dose. The change in serum LDL-C level additionally correlated inversely with the mean GH dose and duration of hypopituitarism and positively with UK citizenship. CONCLUSIONS: Baseline status could, with moderate strength, predict the responsiveness in the same variable whereas it could not, or only weakly, predict the response in other variables. Therefore, when the decision to start GH replacement is undertaken, as many outcome variables as possible should be evaluated in order to adequately evaluate the likelihood of clinical benefit. Finally, women have a similar response to GH replacement as men when individualised GH dosing schedules are employed and should therefore be selected for GH therapy to a similar extent.

Relation between weight loss and causes of death in patients with cardiovascular disease: finding from the SCOUT trial.

AIMS: Obesity is associated with an increased incidence of mortality. The Sibutramine Cardiovascular Outcomes (SCOUT) trial can provide the first evidence of the effect of intentional weight loss on mortality in an obese population at high risk. METHODS: SCOUT was a randomized, double-blind, placebo-controlled trial testing sibutramine vs. placebo. Eligibility for the trial required both men and women aged at least 55 years, with BMI of at least 27 kg/m and 45 kg/m or less. Study participants with type 2 diabetes mellitus (T2DM) only should have at least one other risk factor defined as hypertension, dyslipidaemia, smoking, or diabetic nephropathy, and/or they had a history of cardiovascular disease. Study participants were stratified in three groups: patients with T2DM, patients with a prior cardiovascular event but without diabetes, and patients with both T2DM and a prior cardiovascular event.The relationship between weight loss and mortality (all-cause, cardiovascular, and noncardiovascular) was investigated with Cox regression models. RESULTS: The main study showed that all-cause mortality was not different in patients allocated to sibutramine or placebo. This ancillary analysis demonstrates that there is a general trend showing higher mortality in patients with the greatest weight loss (weight reduction >10 kg) and in those with increasing weight (>1 kg). If integrated weight loss (area under the curve from baseline to 12 months) is used, these observations are confirmed. The impact of substantial weight loss on mortality is marked in those dying of noncardiovascular causes, specifically cancer. CONCLUSION: The relationship between weight change and mortality differs for cardiovascular and noncardiovascular mortality.