Predictors of weight loss and maintenance during 2 years of treatment by sibutramine in obesity. Results from the European multi-centre STORM trial. Sibutramine Trial of Obesity Reduction and Maintenance.

BACKGROUND: In this report we assess pre-treatment determinants of weight loss and maintenance outcome in The Sibutramine Trial of Obesity Reduction and Maintenance (STORM), a 2 y randomized, double-blind, placebo-controlled, European multicenter study examining the effect of sibutramine (Sib) on inducing and maintaining weight loss in obese subjects. MATERIAL: A total of 605 obese patients (BMI: 30-45 kg/m2) of both gender were included from eight European centers and treated for 24 months. The patients were treated for the initial 6 months by Sib (10 mg/day) and a low-fat low-energy, individualized diet (600 kcal/day deficit). The 467 patients who achieved >5% weight loss after 6 months were randomized 3∶1 to Sib (10 mg/day) (Sib/Sib) and placebo (Sib/Pla) for weight maintenance over a further 18 months. MAIN OUTCOME AND ANALYSES: Pre-treatment individual characteristics were assessed as predictors of 6 months weight loss (kg) and 24 months weight maintenance using simple and multivariate correlation and regression analyses. RESULTS: In univariate analyses, the 6 month weight loss (n=505) was positively associated with pre-treatment body weight (r=0.27), height (r=0.18), fat-free mass (r=0.21) (all P<0.001), fat mass (r=0.13, P<0.03), and resting metabolic rate (r=0.13, P<0.003). However, no relation was found with age, gender, smoking status, age at onset of obesity, or number of previous slimming attempts. The same predictors were found for weight change to endpoint in the Sib/Sib group (n=350), while no predictors were identified in the Sib/Pla (n=114). In the multivariate regression analysis only pre-treatment body weight predicted weight loss at 6 months (P<0.001). Weight change (kg) to 24 month was predicted by: 4.34+0.07*body weight (kg)-4*treatment (Sib=1, Pla=0)-0.06*age (y), (r2=8%, P<0.001). CONCLUSION: Only pre-treatment body weight seems to be an important independent predictor of 6 months weight loss and 24 month weight maintenance in this study on diet and Sib. As only 8% of the variation in 24 months weight change could be explained by the predictors, the clinical value of this information is limited.

Obesity as a medical problem.

Obesity is now so common within the world's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. In particular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing disorders. Obesity is defined by a body-mass index (weight divided by square of the height) of 30 kg m(-2) or greater, but this does not take into account the morbidity and mortality associated with more modest degrees of overweight, nor the detrimental effect of intra-abdominal fat. The global epidemic of obesity results from a combination of genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals, but an epidemic that threatens global well being.

Rating the appropriateness of coronary angiography, coronary angioplasty and coronary artery bypass grafting: the ACRE study. Appropriateness of Coronary Revascularisation study.

BACKGROUND: Previous studies investigating the appropriateness of invasive management of coronary disease had not reported the internal consistency of their ratings and may now be out of date. The aim of this study was to measure the influence of clinical factors on contemporary ratings of the appropriateness of coronary angiography, percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) in the Appropriateness of Coronary Revascularisation (ACRE) study. METHODS: The Delphi-RAND technique was used, in which an expert panel (four cardiologists, three cardiothoracic surgeons, a general physician and a general practitioner), meeting in 1995, rated mutually exclusive indications (n = 2178 for angiography, n = 995 for PTCA and n = 984 for CABG). The main outcome measures were the appropriateness category (inappropriate, uncertain or appropriate) for each of the three procedures and treatment preference. RESULTS: For revascularization, the strongest determinant of inappropriateness was coronary anatomy. The odds ratio (OR) for inappropriate PTCA was 10.6 (95 per cent confidence interval (CI) 4.8-23.5) for the effect of left main stem or three-vessel disease versus single-vessel disease, and for CABG it was 0.06 (95 per cent CI 0.03-0.15). The number of diseased vessels was strongly related to preference for medical, PTCA or CABG treatment (p for linear trend <0.001). Mild versus severe anginal symptoms were associated with inappropriate angiography (OR 2.0 (95 per cent CI 0.9-9.8), although this effect was stronger when only the cardiologists' ratings were considered (OR 10.1 (95 per cent CI 2.4-42.6)). CONCLUSION: These are the first UK ratings of appropriateness covering all three procedures. The associations with clinical factors provide evidence of the internal consistency of these ratings. Prospective validation of these ratings against clinical outcomes is under way in the ACRE study.

Neurotrophin-3 is increased in skin in human diabetic neuropathy.

Neurotrophin-3 (NT-3), a member of the neurotrophin family, has been shown to be necessary for the development of muscle spindle and Merkel cell afferent nerve fibres in animal models. The presence of NT-3 in the suprabasal epidermis, where many unmyelinated sensory fibres terminate, has been shown for the first time. As these fibres are affected in early diabetic neuropathy and a clinical trial of recombinant human NT-3 in diabetic neuropathy is in progress, the concentrations of endogenous NT-3 in skin of 24 patients at different stages of diabetic polyneuropathy have been investigated. NT-3 concentrations, measured with a specific immunoassay, were significantly higher in affected skin biopsies from patients with diabetic neuropathy than matched control skin (diabetic skin 6.32 (1.18) pg/mg v control skin 1.28 (0.05) (mean (SEM)); p<0.004, Mann-Whitney U test), particularly in the later stages. The optical density of NT-3-immunostaining was also significantly greater in the epidermis in diabetic patients (diabetic epidermis 0.30 (0.06) v controls 0.24 (0.01); p<0.02). No correlation was found between individual quantitative sensory tests and the increase of NT-3 concentration. The increase of NT-3 seems to reflect the degree of skin denervation in diabetic neuropathy, and may represent a compensatory mechanism. The concentrations of NT-3 in other peripheral targets deserve study in diabetic neuropathy.

Leptin levels do not change acutely with food administration in normal or obese subjects, but are negatively correlated with pituitary-adrenal activity.

BACKGROUND: Leptin is a peptide secreted by white adipose tissue which has been shown to have a major influence on body weight regulation, while animal studies have revealed widespread interconnections between leptin and other endocrine systems, especially with insulin. However, its acute regulation has been little studied in the human. We have therefore investigated the effect of a 1000 kcal meal and fasting on the levels of leptin, insulin and cortisol, in both normal and obese subjects. SUBJECTS AND DESIGN: We have studied the effect of food and fasting on circulating leptin levels in 20 subjects of normal body mass index (BMI range 18-25) and in a group of 12 moderately-severely obese subjects (BMI range 34-61). We also studied the effect of food and fasting in a patient both before and after the successful removal of a pancreatic insulinoma as a model of excess insulin secretion. RESULTS: Mean leptin levels were significantly higher in the obese than in the lean group (42.7 +/- 3.41 vs 5.35 +/- 1.55 micrograms/l, mean +/- SEM; P < 0.001), and showed a positive correlation with body mass index (r = +0.71; P < 0.001). Frequent (every 20 minutes) sampling for 3 hours after food did not show any acute changes in circulating leptin levels. On the fasting day we observed a small but significant fall in circulating leptin levels in the last 4 hours of a 20-hour fast in our subjects as a group (92 +/- 0.03% of basal, P = 0.03); however, in the lean subjects the fall was greater (86 +/- 0.04% of basal, P = 0.02) than in the obese, where it did not reach statistical significance (96 +/- 0.05% of basal). Pre-meal and peak insulin levels showed a positive correlation with circulating mean leptin levels (r = +0.65; P < 0.001 and r = +0.78; P < 0.001, respectively) in all subjects, while pre-meal and peak serum cortisol levels showed an inverse relation with leptin levels (r = -0.53; P = 0.002 and r = -0.41; P = 0.02, respectively); this effect was independent of BMI in the obese subjects. In the patient with the insulinoma the markedly elevated insulin and leptin levels measured before the operation returned to normal after removal of the tumour, in accord with reports of experimental animal data that long-term insulin excess per se is associated with increased circulating leptin concentrations. CONCLUSION: Leptin is a robust indicator of BMI and insulin levels, both basal and stimulated, but does not change acutely following food. Fasting causes a proportionately greater decline in leptin levels in lean subjects than in obese subjects. Circulating leptin is inversely correlated with the activity of the hypothalamo-pituitary-adrenal axis: whether this is a direct influence of leptin on hypothalamo-pituitary-adrenal activity, or whether both are indirect indicators of body fat stores, requires further investigation.

trkA and trkC expression is increased in human diabetic skin.

Nerve growth factor (NGF) is reduced in epidermal keratinocytes in human diabetic skin, and this decrease has been related to dysfunction of cutaneous sensory fibres. In vitro studies show that keratinocytes express both NGF and its high-affinity receptor, trkA, and that NGF may increase keratinocyte proliferation and its own expression via an autocrine loop. However, the level of trkA expression in vivo by keratinocytes in normal and diabetic skin is unknown. We have therefore measured trkA expression in calf skin biopsies from patients with early subclinical diabetic neuropathy and control subjects, using in situ hybridisation combined with image analysis quantification. Expression of trkC was also studied, as its endogenous ligand neurotrophin-3 (NT-3) is related to NGF, and is present in human epidermis. Hybridisation signal was seen for both trkA and trkC localised throughout the epidermal layer of control skin, with a higher density of silver grain deposition observed for trkA mRNA. However, in diabetic epidermis there was a significant increase (P < 0.001) for both trk A (control, 0.178 +/- 0.013; diabetic, 0.304 +/- 0.032; mean silver grain counts/microm2 +/- SEM) and trkC expression (controls, 0.059 +/- 0.004; diabetics, 0.191 +/- 0.010). The up-regulation of epidermal trk receptors may result from decreased autocrine neurotrophin action, and could represent a compensatory mechanism.

Comparison of case fatality in south Asian and white patients after acute myocardial infarction: observational study.

OBJECTIVE: To compare mortality in south Asian (Indian, Pakistani, and Bangladeshi) and white patients in the six months after hospital admission for acute myocardial infarction. DESIGN: Observational study. SETTING: District general hospital in east London. PATIENTS: 149 south Asian and 313 white patients aged < 65 years admitted to the coronary care unit with acute myocardial infarction from 1 December 1988 to 31 December 1992. MAIN OUTCOME MEASURE: All cause mortality in the first six months after myocardial infarction. RESULTS: The admission rate in the south Asians was estimated to be 2.04 times that in the white patients. Most aspects of treatment were similar in the two groups, except that a higher proportion of the south Asians received thrombolytic drugs (81.2% v 73.8%). After adjustment for age, sex, previous myocardial infarction, and treatment with thrombolysis or aspirin, or both, the south Asians had a poorer survival over the six months from myocardial infarction (hazard ratio 2.02 (95% confidence interval 1.14 to 3.56), P = 0.018), but a substantially higher proportion were diabetic (38% v 11%, P < 0.001), and additional adjustment for diabetes removed much of their excess risk (adjusted hazard ratio 1.26 (0.68 to 2.33), P = 0.47). CONCLUSION: South Asian patients had a higher risk of admission with myocardial infarction and a higher risk of death over the ensuing six months than the white patients. The higher case fatality among the south Asians, largely attributable to diabetes, may contribute to the increased risk of death from coronary heart disease in south Asians living in Britain.

A comparison of the effects of human and ovine corticotropin-releasing hormone on the pituitary-adrenal axis.

To compare the clinical efficacy of ovine and human sequence corticotropin-releasing hormone (CRH), we examined the effects of both peptides on ACTH and cortisol secretion in normal human volunteers, obese subjects, and patients with pituitary-dependent (Cushing's disease) and adrenal-dependent Cushing's syndrome. All subjects in each group were studied twice in random order. One hundred micrograms of CRH were administered as an iv bolus through an in-dwelling forearm cannula at 0930 h, and thereafter, blood was drawn every 15 min for 2 h for the measurement of ACTH and cortisol. In the normal subjects, the peak ACTH, peak incremental ACTH, and mean area under the curve after CRH treatment were greater with ovine CRH than human CRH, although there was no difference in the cortisol response, however it was analyzed. There was no difference in the ACTH or cortisol response to the two preparations in the obese subjects, and no significant difference was found, for either cortisol or ACTH, between obese subjects and normal volunteers. With both varieties of CRH, Cushing's disease resulted in greater responses for ACTH and cortisol than those seen in the other 2 groups (P < 0.001 for all comparisons), but there was no difference between the sequences. However, a significant cortisol response, defined as an increase of greater than 4 times the coefficient of variation of the assay (24%), was seen in all 10 Cushing's patients with human CRH, but in only 8 with ovine CRH. In 3 patients with adrenal tumors, serum cortisol did not change after the administration of either preparation, whereas plasma ACTH remained undetectable throughout the study. We suggest that although ovine sequence CRH causes more prolonged and greater ACTH, and possibly cortisol, secretion compared to human CRH, the discriminatory value of the CRH test, in terms of either the diagnosis or differential diagnosis of Cushing's syndrome, is comparable for the two peptide sequences.

Hormones and obesity.

This chapter has reviewed the evidence for obesity being characterized by distinct patterns of hormonal changes related to both the degree of obesity and the distribution of fat tissue. Many of these changes are also seen in subjects with Cushing's and polycystic ovary syndromes, in particular hyperinsulinaemia, alterations in adrenocortical activity and sex steroid secretion and binding. Animal models of obesity provide evidence to suggest the possibility of a primary abnormality of hypothalamic-pituitary function as a basis to corpulence and this cannot be excluded in the human situation. Nevertheless, abdominal distribution of adiposity plays a significant role in establishing a vicious cycle of metabolic events which may perpetuate both the obese state and PCOS. It is of interest that the additive genetic effect for total body fat is about 25% whereas the heritability of subcutaneous truncal-abdominal fat is about 30-35%, and may possibly be higher (Bouchard et al, 1993). Upper body obesity is characterized by large adipose cells with higher LPL activity, elevated basal and stimulated lipolysis but a low antilipolytic effect of insulin. The results from preliminary investigations of potential candidate genes suggest a possible genetic basis to hyperinsulinaemia/insulin resistance found in upper body obesity but further studies of greater numbers are required for confirmation. It is hoped that the findings from such molecular studies will shed additional light on both the genetic background to obesity and the complex hormonal alterations seen at the tissue level. This should provide the confirmation of a unifying theory for the causal factors associated with obesity and related conditions.

Long-term symptomatic relief of postprandial hypoglycaemia following gastric surgery with a somatostatin analogue.

Somatostatin has been shown to be effective in the management of the dumping syndrome and there have been reports of the effective use of long acting somatostatin analogue in the management of this condition. However, there have been few reports of the prolonged use of a somatostatin analogue in the late dumping syndrome. We describe a patient in whom this management provided good long term symptomatic relief which was confirmed biochemically.

The use of CRF-41 in the differential diagnosis of Cushing's syndrome and obesity.

The use of a standard CRF test, using 100 micrograms i.v. synthetic ovine CRF-41, has been assessed in 22 patients with surgically-proven Cushing's disease and one patient with the ectopic ACTH syndrome secondary to a bronchial carcinoid. Three of the 22 patients, and the single patient with the ectopic ACTH syndrome, failed to produce a rise in serum cortisol to above the normal range in response to CRF-41. However, 18/22 patients with Cushing's disease had an enhanced cortisol response to CRF, including four patients who were resistant to high-dose dexamethasone. One patient with Cushing's disease responded to CRF-41 with an excessive cortisol response on one occasion, and a rise within the normal range on a second. Ten patients with simple obesity (mean weight 101 kg) were given CRF 0.5 microgram/kg, and their results compared to a control group of seven normal weight females (mean weight 58 kg). Peak serum cortisol responses to CRF were significantly less than in the control group, even when the dose was increased to 1 microgram/kg in six of the obese patients. Peak plasma ACTH responses were not significantly different between control and patient groups. It is concluded that the serum cortisol response to CRF is enhanced in the majority (but not all) of patients with Cushing's disease, and is attenuated in simple obesity. The reason for this attenuation requires further study.

Relationship between retinopathy and glycaemic control in insulin-dependent and non-insulin-dependent diabetes.

The possible relationship between antecedent diabetic control, as determined by serial glycosylated haemoglobin (HbA1) measurements, and diabetic retinopathy was examined in 40 insulin-dependent and 41 non-insulin-dependent diabetics selected consecutively from our clinic population. Multiple logistic regression analysis demonstrated a significant association between mean HbA1 and prevalence of retinopathy in both groups of patients. This association was independent of duration of diabetes which was also significantly associated with retinopathy prevalence. Hypertension and smoking were not obvious risk factors in this group of patients; an apparent association of hypertension and diabetes was entirely accounted for by a positive relationship between the presence of hypertension and duration of diabetes.

Disparity between glucose-dependent insulinotropic polypeptide and insulin responses in obese man.

Studies were carried out in 32 obese patients and 30 normal-weight control subjects to ascertain the response of glucose-dependent insulinotropic polypeptide (GIP) and insulin to (1) oral and intravenous glucose (10 obese and 10 control subjects), (2) oral fat and intravenous glucose (eight obese and six control subjects) and (3) mixed test meal (14 obese and 14 control subjects). Basal mean insulin was higher in the obese (99 pmol/l) than in the control group (40 pmol/l), but fasting blood glucose and GIP were not significantly different from normal. The total integrated response of insulin in obese subjects after oral glucose was 54.1 versus 33.3 nmol . l-1 . h-1 in control subjects; glucose and GIP responses were similar in both groups. After intravenous glucose the integrated insulin response was 8.8 in the obese versus 5.0 nmol . l-1 . h-1 in control subjects; GIP was unaffected by intravenous glucose and glucose levels were similar. Following oral fat and intravenous glucose, insulin secretion was again abnormal in the obese, 24.5 versus 7.3 nmol . l-1 . h-1 in controls, but GIP responses were normal. However, the control subjects became hypoglycaemic after this test: blood glucose 2.8 mmol/l at 150 min compared with 4.6 mmol/l in the obese group. The insulin response to a mixed meal was also abnormal in obesity.

The effect of weight loss on sex steroid secretion and binding in massively obese women.

We have previously reported increased testosterone and androstenedione concentrations and decreased sex hormone binding globulin (SHBG) concentrations in the plasma of massively obese women. We now report that these plasma hormone concentrations return to normal in twelve of the same women after substantial weight reduction and these changes are associated with more normal menstrual cycles. We conclude that body weight and fat are important determinants of sex steroid secretion and binding and thus influence menstrual function.

Changes in thyroid hormones in obese women following jejuno-ileal bypass surgery.

The serum concentrations of thyroxine (T4), 3,5,3'-triiodothyronine (T3) and 3,3'5'-triiodothyronine (reverse T3) in 10 massively obese women were studied before and at intervals for one year after jejuno-ileal bypass operation. A significant rise in T3 (P less than 0.01) over the immediately preoperative value, a significant fall in rT3 (P less than 0.01) but no significant change in T4 was found during the post-recovery follow-up period. It is concluded that maintaining a relatively high T3 level following jejuno-ileal bypass surgery may contribute to the substantial weight reduction achieved by patients after this operation.

Fungal endocarditis after homograft valve replacement: difficulties in diagnosis and treatment.

Fungal endocarditis is an uncommon but important problem after cardiac surgery. Two cases of fungal endocarditis after homograft valve replacement are reported. In both patients prolonged periods of antifungal chemotherapy with apparently satisfactory clinical responses ultimately failed to eradicate the infection. Both patients remain free of infection two years after excision of the infected valves and further chemotherapy. The value of serial estimations of fungal antibody titres in diagnosis and treatment is demonstrated and the necessity for early operation is emphasised.

Abnormal sex steroid secretion and binding in massively obese women.

We have measured the plasma concentrations of sex steroids and sex hormone-binding globulin (SHBG) in twenty-three massively obese women and ten age-matched lean female volunteers. In the obese women increased plasma testosterone (obese 3.2 +/- 0.5 nmol/l controls 1.7 +/- 0.5 nmol/l, P less than 0.3) and androstenedione concentrations (obese 9.7 +/- 1.2 nmol/l, controls 4.4 +/- 0.6 nmol/l, P = less than 0.01) an increased ratio of oestrone:oestradiol (obese 2.4 +/- 0.4, controls 1.0 +/- 0.1, P = less than 0.1) and decreased SHBG levels (obese 30 +/- 4 nmol/l, controls 60 +/- 8 nmol/l, P = less than 0.001) were found. Obesity differed from the polycystic ovary syndrome (in which a similar pattern of changes of sex steroid concentrations and binding are seen) in that it was associated with normal increases in serum luteinizing hormone (LH) follicle stimulating hormone (FSH) levels in response to the administration of LHRH. We conclude that the common occurrence of menstrual abnormalities in obesity results from abnormal secretion and binding of sex steroids. In addition, the unaltered secretion of LH and FSH in the presence of such changes is evidence for a disorder of hypothalamic function.