Structure of proof of concept studies that precede a nonalcoholic steatohepatitis development program.

Surrogate endpoints for clinical proof of concept (POC) trials in nonalcoholic steatohepatitis (NASH) are based upon expert pathological review of liver biopsies. During early development, these long-term POC studies (≥48 weeks) add cost and time to the "Go/No Go" decision process. However, it is possible to conduct short-term noninvasive POC studies utilizing biomarkers and magnetic resonance imaging. Here, we discuss the use of shorter noninvasive POC studies relative to biopsy-driven studies for drug development in NASH.

A comparison of efficacy and safety of vildagliptin and gliclazide in combination with metformin in patients with Type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study.

AIM: To demonstrate non-inferiority of vildagliptin compared with gliclazide, as an add-on therapy, in patients with Type 2 diabetes inadequately controlled with metformin in a 52-week, randomized, double-blind, active-controlled study. METHODS: Patients receiving a stable dose of metformin (> or = 1500 mg) were randomized (1 : 1) to receive vildagliptin (50 mg twice daily; n = 513) or gliclazide (up to 320 mg/day; n = 494). RESULTS: Non-inferiority of vildagliptin was demonstrated (95% confidence interval -0.11%, 0.20%) with a mean change (se) from baseline glycated haemoglobin (HbA(1c)) (approximately 8.5% in both groups) to a 52-week endpoint of -0.81% (0.06) with vildagliptin and -0.85% (0.06) with gliclazide. Although a similar proportion of patients reached HbA(1c) < 7.0%, the total number of hypoglycaemic events was lower in the vildagliptin group (6 vs. 11 events). Vildagliptin was non-inferior (margin 0.6 mmol/l) to gliclazide in reducing fasting plasma glucose (1.31 vs. 1.52 mmol/l, P = 0.257). The overall incidence of any adverse events was similar in both groups (approximately 61%), but the number of serious adverse events was higher in the gliclazide group (8.7 vs. 6.7%). The number of patients who discontinued as a result of an unsatisfactory effect was higher in the vildagliptin group (n = 22 vs. 13, respectively) compared with gliclazide, but vildagliptin did not induce weight gain. CONCLUSION: In patients with Type 2 diabetes inadequately controlled with metformin, addition of vildagliptin provided similar HbA(1c)-lowering efficacy compared with gliclazide after 52 weeks of treatment. Although both treatments were well tolerated, vildagliptin-treated patients had fewer hypoglycaemic events and did not gain weight.

[Underestimation of renal risk in cardiology clinics. RICAR study]. / Infravaloración del riesgo renal en consultas de cardiología. Estudio RICAR.

AIMS: The aim of this study was to assess the rate of patients attended in cardiology outpatient clinics in whom microalbumine or glomerular filtration rate had been determined, at least once, in the previous 12 months. METHODS: It was an observational, transversal, multicentric study. 1224 patients were included from 124 centers in Spain. Epidemiological, anthropometric, analytic and electrocardiographic data were recruited. Glomerular filtration rate was calculated thereafter by means of the simplified equation of the MDRD. Results. Microalbumine was determined in 34% of the patients, of those 49% had positive microalbumine. Microalbumine rates were higher in patients with diabetes, heart failure, atrial fibrillation, peripheral artery disease or serum creatinine levels > 1.3 mg/dl. However, only young patients, diabetics and those with left ventricular hypertrophy had this exam performed more often. The glomerular filtration rate was determined in 11% of the patients. 30% of the population had moderate or severe renal dysfunction (filtration rate < 60 ml/min) and only 21% of the population hat normal renal function (filtration rate > 90 ml/min). Glomerular filtration rate was assessed more frequently in patients with serum creatinine > 1.3 mg/dl and those with history of heart failure. CONCLUSIONS: The prevalence of renal dysfunction in hypertensive patients attended in Cardiology clinics is high. However, the methods recommended for early detection of renal dysfunction are scarcely used by cardiologists. These figures do not improve significantly in high risk patients.

Impacto del tratamiento con irbesartán sobre la reducción del riesgo cardiovascular de pacientes hipertensos en España. Estudio KORAL-HTA / Impact of treatment with irbesartan on reduction of cardiovascular risk in hypertensive patients in Spain. Koral-HTA study

Objetivos. Evaluar la eficacia de irbesartán para alcanzar los objetivos de presión arterial (PA) establecidos por las guías y en reducir la microalbuminuria (MAU) en pacientes hipertensos no controlados. Evaluar este efecto tanto en pacientes diabéticos como no diabéticos y en diferentes rangos de índice de masa corporal (IMC). Estudiar el impacto de este tratamiento sobre el riesgo coronario global (RCG) valorado mediante las tablas REGICOR. Métodos. KORAL-HTA es un estudio observacional, prospectivo y abierto de 1 año de seguimiento en pacientes hipertensos no controlados con al menos otro factor de riesgo cardiovascular atendidos en Unidades de Hipertensión en toda España. Resultados. Estudiamos 1.657 pacientes (el 59,5 % de hombres; edad media (desviación estándar [DE]): 60,3 [12,0] años). Un 48,4 % presentaba diabetes mellitus (DM), un 48,2 % dislipemia y MAU un 63,6 %. Un 70 % de los pacientes alcanzó los objetivos de PA (< 140/90 mmHg y < 130/80 mmHg en no DM y DM, respectivamente). La proporción de pacientes con MAU y proteinuria se redujo del 63,6 % al 48,3 % y del 19,4 % al 10,8 %, respectivamente; p < 0,01, en el grupo global, así como en los pacientes con y sin DM, y en los diferentes rangos del IMC. El RCG disminuyó desde (mediana [perc 25-75]) 5,9 (3,0-8,0) y 9,7 (5,0-12,0) basalmente, en no diabéticos y diabéticos, respectivamente, a 4,0 (3,0-5,0) y 5,0 (3,8-7,0), respectivamente, a los 12 meses (p < 0,001). Conclusiones. La reducción de la PA y la MAU con el tratamiento con irbesartán se asocia a una reducción del RCG en los pacientes hipertensos. Este estudio confirma además, en condiciones de práctica clínica, que los beneficios sobre la MAU no se limitan únicamente a los pacientes con DM, sino también a aquellos no diabéticos y son constantes en los diferentes rangos del IMC

Objectives. Evaluate the efficacy of irbesartan to reach the blood pressure objectives established in the guides and reduce microalbuminuria (MAU) in uncontrolled hypertensive patients. Evaluate this effect in both diabetic and non-diabetic patients and in different BMI ranges. Study the impact of this treatment on global coronary risk (GCR) assessed with the REGICOR tables. Methods. KORAL-HTA is an observational, prospective, open-label 1-year follow-up study in uncontrolled hypertensive patients with at least one other cardiovascular risk factor seen in hypertensive units in all Spain. Results. We studied 1,657 patients (59.5 % men; mean age (SD): 60.3 (12.0) years). A total of 48.4 % had DM, 48.2 % dyslipidemia and 63.6 % MAU. Seventy percent of the patients achieved the BP objectives (< 140/90 mmHg and < 130/80 mmHg in non-DM and DM, respectively). The proportion of patients with MAU and proteinuria decreased from 63.6 % to 48.3 % and from 19.4 % to 10.8 %, respectively; p < 0.01, in the global group and in patients with and without DM, and in the different BMI ranges. GCR decreased from (median [perc 25-75]) 5.9 (3.0-8.0) and 9.7 (5.0-12.0) at baseline, in non-diabetics and diabetics, respectively to 4.0 (3.0-5.0) and 5.0 (3.8-7.0), respectively, at 12 months (p < 0.001). Conclusions. BP and MAU decrease with Irbesartan treatment is associated to a decrease in GCR in hypertensive patients. This study also confirms under clinical practice conditions that the benefits on MAU are not only limited to patients with DM but also to the non-diabetics and are constant in the different BMI ranges

Smoking cessation and weight gain.

Cigarette smoking is the single most important preventable cause of death and illness. Smoking cessation is associated with substantial health benefits. Weight gain is cited as a primary reason for not trying to quit smoking. There is a great variability in the amount of weight gain but younger ages, lower socio-economic status and heavier smoking are predictors of higher weight gain. Weight change after smoking cessation appears to be influenced by underlying genetic factors. Besides, weight gain after smoking cessation is largely because of increased body fat and some studies suggest that it mostly occurs in the subcutaneous region of the body. The mechanism of weight gain includes increased energy intake, decreased resting metabolic rate, decreased physical activity and increased lipoprotein lipase activity. Although there is convincing evidence for the association between smoking cessation and weight gain, the molecular mechanisms underlying this relationship are not well understood. This review summarizes current information of the effects of nicotine on peptides involved in feeding behaviour. Smoking was shown to impair glucose tolerance and insulin sensitivity and cross-sectional studies have demonstrated that smokers are insulin-resistant and hyperinsulinaemic, as compared with non-smokers. Smoking cessation seems to improve insulin sensitivity in spite of the weight gain. Nicotine replacement - in particular nicotine gum - appears to be effective in delaying post-cessation weight gain. In a group of women who failed to quit smoking because of weight gain, a dietary intervention (intermittent very-low-calorie diet) plus nicotine gum showed to both increase success rate in terms of smoking cessation and prevent weight gain. On the other hand, body weight gain at the end of treatment was significantly lower in the patients receiving bupropion or bupropion plus nicotine patch, compared with placebo. Studies with new drugs available for the treatment of obesity - sibutramine and orlistat - are warranted.

Obesity prevalence and trends in Latin-American countries.

The prevalence of obesity in some lower-income and transitional countries is as high as, or even higher than, the prevalence reported in developed nations, and it seems to be increasing rapidly. In most countries, the prevalence of obesity is higher in women than in men, and higher in urban than in rural areas. Preobesity prevalence is very high in most Latin-American countries. Sixty per cent of the population in Venado Tuerto (Argentina) has a body mass index (BMI) of > or = 25 kg m-2, as do 35% of the population in Brazil, 60% in Mexico, 68% in Paraguay and 53% in Peru. Trends are available from Brazil, where marked increases in the prevalence of obesity have occurred, except in women from higher-income groups. Women from the higher-income quartiles in urban regions experienced a marked reduction in obesity prevalence from 1989 to 1997 (12.8 to 9.2%). Although data in children is scant, the prevalence of undernutrition is decreasing and the prevalence of obesity is high also in Latin-American children. The prevalence of obesity is high even in minority Indian groups. Rapid changes in dietary structure (in particular associated with urbanization) and major changes in the levels of physical activity, both occupationally and during leisure time, may explain these changes.

Low plasma leptin concentration and low rates of fat oxidation in weight-stable post-obese subjects.

OBJECTIVE: A low resting metabolic rate for a given body size and composition, a low rate of fat oxidation, low levels of physical activity, and low plasma leptin concentrations are all risk factors for body weight gain. The aim of the present investigation was to compare resting metabolic rate (RMR), respiratory quotient (RQ), levels of physical activity, and plasma leptin concentrations in eight post-obese adults (2 males and 6 females; 48.9 +/- 12.2 years; body mass index [BMI]: 24.5 +/- 1.0 kg/m2; body fat 33 +/- 5%; mean +/- SD) who lost 27.1 +/- 21.3 kg (16 to 79 kg) and had maintained this weight loss for > or =2 months (2 to 9 months) to eight age- and BMI-matched control never-obese subjects (1 male and 7 females; 49.1 +/- 5.2 years; BMI 24.4 +/- 1.0 kg/m2; body fat 33 +/- 7%). RESEARCH METHODS AND PROCEDURES: Following 3 days of weight maintenance diet (50% carbohydrate and 30% fat), RMR and RQ were measured after a 10-hour fast using indirect calorimetry and plasma leptin concentrations were measured using radioimmunoassay. Levels of physical activity were estimated using an accelerometer over a 48-hour period in free living conditions. RESULTS: After adjustment for fat mass and fat-free mass, post-obese subjects had, compared with controls, similar levels of physical activity (4185 +/- 205 vs. 4295 +/- 204 counts) and similar RMR (1383 +/- 268 vs. 1430 +/- 104 kcal/day) but higher RQ (0.86 +/- 0.04 vs. 0.81 +/- 0.03, p < 0.05). Leptin concentration correlated positively with percent body fat (r = 0.57, p < 0.05) and, after adjusting for fat mass and fat-free mass, was lower in post-obese than in control subjects (4.5 +/- 2.1 vs. 11.6 +/- 7.9 ng/mL, p < 0.05). DISCUSSION: The low fat oxidation and low plasma leptin concentrations observed in post-obese individuals may, in part, explain their propensity to relapse.

Predictors of weight gain: the biological-behavioural debate.

The rapidly increasing prevalence of obesity, in spite of an unchanged gene pool, makes it interesting to search for biological factors which increase the susceptibility at the individual level as well as searching for the responsible environmental factors. Among the identified metabolic factors is a low resting metabolic rate for given body size and composition, a high respiratory quotient (RQ) indicating a low fat oxidation and a low spontaneous physical activity, all factors which are regarded as being under substantial genetic influence. Among the environmental factors, it is low levels of physical activity, increasing inactivity and a high fat diet that are probably the most important ones. In this review we have focused on controversies in this area. Understanding the interaction between the constitutional biological factors and the environmentally determined lifestyle factors it is important to produce better options for both the prevention and treatment of obesity.

[Heart rate and physical activity to assess energy expenditure in children]. / Medicion del gasto energetico en niños a partir de la frecuencia cardiaca y actividad.

The aim of the present study was to validate assessment of oxygen consumption (VO2) from heart rate (HR) and physical activity (PA) electronically recorded. Every minute, mean VO2 were validated with indirect calorimetry. We studied 25 children (12 girls, 13 boys), 12.1 +/- 0.7 years old. Measurements were made during about 60 minutes while kids were supine, sitting, standing and walking at four intensities. Minute by minute heart rate was converted to VO2 and energy expenditure using 2 different functions for active and inactive situations. A linear function (VO2 = a + beta HR) was used when counts were 7 or higher and HR higher than a prefixed point (intersection between the 2 line functions). A nonlinear equation (VO2 = a + beta HR3) was used in the remaining minutes. Mean predicted VO2 for every minute were similar to measured VO2 (2 ways interaction ANOVA, p = 0.99). Mean VO2 correlated significantly with VO2 predicted by equation (r = 0.99, p < 0.01). High degree of agreement was found (Bland-Altman comparisons). Combined heart rate and physical activity predicted oxygen consumption with a precision similar to the indirect calorimetric method.

Medicion del gasto energetico en niños a partir de la frecuencia cardiaca y actividad. / [Heart rate and physical activity to assess energy expenditure in children]

The aim of the present study was to validate assessment of oxygen consumption (VO2) from heart rate (HR) and physical activity (PA) electronically recorded. Every minute, mean VO2 were validated with indirect calorimetry. We studied 25 children (12 girls, 13 boys), 12.1 +/- 0.7 years old. Measurements were made during about 60 minutes while kids were supine, sitting, standing and walking at four intensities. Minute by minute heart rate was converted to VO2 and energy expenditure using 2 different functions for active and inactive situations. A linear function (VO2 = a + beta HR) was used when counts were 7 or higher and HR higher than a prefixed point (intersection between the 2 line functions). A nonlinear equation (VO2 = a + beta HR3) was used in the remaining minutes. Mean predicted VO2 for every minute were similar to measured VO2 (2 ways interaction ANOVA, p = 0.99). Mean VO2 correlated significantly with VO2 predicted by equation (r = 0.99, p < 0.01). High degree of agreement was found (Bland-Altman comparisons). Combined heart rate and physical activity predicted oxygen consumption with a precision similar to the indirect calorimetric method.