Efficacy and safety of insulin lispro in obese patients with type 2 diabetes: a retrospective metaanalysis of 7 randomized controlled trials.

OBJECTIVE: To evaluate the efficacy and safety of insulin lispro in the treatment of patients with type 2 diabetes (T2DM) who had a body mass index (BMI) ≥30 kg/m2 (obese) compared with patients with BMIs <30 kg/m2 (nonobese). METHODS: A retrospective analysis of predefined end-points from 7 randomized clinical trials of T2DM patients treated with insulin lispro was performed. The primary efficacy measure was to assess the noninferiority of insulin lispro in obese patients versus nonobese patients as measured by the change in hemoglobin A1C (HbA1c) from baseline to Month 3 (n = 1,518), using a noninferiority margin of 0.4%. The secondary measures included overall hypoglycemia incidence and event rates and relative change in body weight. RESULTS: Mean changes in HbA1c from baseline (9.06% for obese and 8.92% for nonobese) to Month 3 were similar for obese patients (-1.03%) and nonobese (-1.02%), with a least squares (LS) mean difference (95% confidence interval [CI]) of -0.05% (-0.17%, 0.07%; P = .384). The overall incidence of hypoglycemia (53% vs. 63%; P<.001) and rate of hypoglycemia (0.93 vs. 1.76 events per 30 days; P<.001) was significantly lower in obese patients compared with nonobese patients. The 2 BMI cohorts did not demonstrate a significant difference in mean percent changes in body weights (LS mean difference = 0.4% [-0.2%, 0.9%]; P = .202). CONCLUSION: Obese patients with T2DM treated with insulin lispro were able to achieve the same level of glycemic control as their nonobese counterparts, with some evidence supporting a reduced risk of hypoglycemia.

Efficacy and safety of insulin lispro in geriatric patients with type 2 diabetes: a retrospective analysis of seven randomized controlled clinical trials.

BACKGROUND AND AIMS: Glycemic control in geriatric patients with type 2 diabetes (T2DM) remains clinically challenging. The objective of this study was to compare the safety and efficacy of insulin lispro in patients C65 years (geriatric) to those\65 years (non-geriatric), using a metaanalysis of randomized controlled clinical trials (RCT). METHODS: This is a retrospective analysis of predefined endpoints from an integrated database of seven RCTs of T2DM patients treated with insulin lispro. The primary efficacy measure tested the non-inferiority of insulin lispro (geriatric vs. non-geriatric; non-inferiority margin 0.4 %) in terms of hemoglobin A1c (HbA1c) change from baseline to Month 3 (N = 1,525), with change from baseline to Month 6 as a supportive analysis (N = 885). Changes in HbA1c from baseline were evaluated with an analysis of covariance model. Secondary measures included incidence and rate of hypoglycemia, and incidence of cardiovascular events. RESULTS: Mean change in HbA1c from baseline to Month 3 was similar for geriatric (-0.97 %) and non-geriatric patients (-1.05 %); least-square (LS) mean difference (95 % CI) was 0.02 % (-0.11, 0.15 %; p = 0.756). Similar results were observed in patients treated up to Month 6; LS mean difference (95 % CI) was 0.07 % (-0.12, 0.26 %; p = 0.490). Decrease in HbA1c from baseline to Months 3 and 6 was non-inferior in geriatric compared with non-geriatric patients. There were no significant differences in the incidence and the rate of hypoglycemia, incidence of cardiovascular events, or other serious adverse events including malignancy, post-baseline between the two cohorts. CONCLUSION: Key measures of efficacy and safety in geriatric patients with T2DM were not significantly different from non-geriatric patients when utilizing insulin lispro. Insulin lispro may be considered a safe and efficacious therapeutic option for the management of T2DM in geriatric patients.

Functional changes in adipose tissue in a randomised controlled trial of physical activity.

BACKGROUND: A sedentary lifestyle predisposes to cardiometabolic diseases. Lifestyle changes such as increased physical activity improve a range of cardiometabolic risk factors. The objective of this study was to examine whether functional changes in adipose tissue were related to these improvements. METHODS: Seventy-three sedentary, overweight (mean BMI 29.9 ± 3.2 kg/m2) and abdominally obese, but otherwise healthy men and women (67.6 ± 0.5 years) from a randomised controlled trial of physical activity on prescription over a 6-month period were included (control n = 43, intervention n = 30). Detailed examinations were carried out at baseline and at follow-up, including fasting blood samples, a comprehensive questionnaire and subcutaneous adipose tissue biopsies for fatty acid composition analysis (n = 73) and quantification of mRNA expression levels of 13 candidate genes (n = 51), including adiponectin, leptin and inflammatory cytokines. RESULTS: At follow-up, the intervention group had a greater increase in exercise time (+137 min/week) and a greater decrease in body fat mass (-1.5 kg) compared to the control subjects (changes of 0 min/week and -0.5 kg respectively). Circulating concentrations of adiponectin were unchanged, but those of leptin decreased significantly more in the intervention group (-1.8 vs -1.1 ng/mL for intervention vs control, P < 0.05). The w6-polyunsaturated fatty acid content, in particular linoleic acid (18:2w6), of adipose tissue increased significantly more in the intervention group, but the magnitude of the change was small (+0.17 vs +0.02 percentage points for intervention vs control, P < 0.05). Surprisingly leptin mRNA levels in adipose tissue increased in the intervention group (+107% intervention vs -20% control, P < 0.05), but changes in expression of the remaining genes did not differ between the groups. CONCLUSIONS: After a 6-month period of increased physical activity in overweight elderly individuals, circulating leptin concentrations decreased despite increased levels of leptin mRNA in adipose tissue. Otherwise, only minor changes occurred in adipose tissue, although several improvements in metabolic parameters accompanied the modest increase in physical activity.

Normal weight obesity: a risk factor for cardiometabolic dysregulation and cardiovascular mortality.

AIMS: We hypothesized that subjects with a normal body mass index (BMI), but high body fat (BF) content [normal weight obesity (NWO)], have a higher prevalence of cardiometabolic dysregulation and are at higher risk for cardiovascular (CV) mortality. METHODS AND RESULTS: We analysed 6171 subjects >20 years of age from the Third National Health and Nutrition Examination Survey (NHANES III) and the NHANES III mortality study, whose BMI was within the normal range (18.5-24.9 kg/m(2)), and who underwent a complete evaluation that included body composition assessment, blood measurements, and assessment of CV risk factors. Survival information was available for >99% of the subjects after a median follow-up of 8.8 years. We divided our sample using sex-specific tertiles of BF%. The highest tertile of BF (>23.1% in men and >33.3% in women) was labelled as NWO. When compared with the low BF group, the prevalence of metabolic syndrome in subjects with NWO was four-fold higher (16.6 vs. 4.8%, P < 0.0001). Subjects with NWO also had higher prevalence of dyslipidaemia, hypertension (men), and CV disease (women). After adjustment, women with NWO showed a significant 2.2-fold increased risk for CV mortality (HR = 2.2; 95% CI, 1.03-4.67) in comparison to the low BF group. CONCLUSION: Normal weight obesity, defined as the combination of normal BMI and high BF content, is associated with a high prevalence of cardiometabolic dysregulation, metabolic syndrome, and CV risk factors. In women, NWO is independently associated with increased risk for CV mortality.

Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic US population.

AIMS: Prospective studies indicate that apolipoprotein measurements predict coronary heart disease (CHD) risk; however, evidence is conflicting, especially in the US. Our aim was to assess whether measurements of apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) can improve the ability to predict CHD death beyond what is possible based on traditional cardiovascular (CV) risk factors and clinical routine lipid measurements. METHODS AND RESULTS: We analysed prospectively associations of apolipoprotein measurements, traditional CV risk factors, and clinical routine lipid measurements with CHD mortality in a multi-ethnic representative subset of 7594 US adults (mean age 45 years; 3881 men and 3713 women, median follow-up 124 person-months) from the Third National Health and Nutrition Examination Survey mortality study. Multiple Cox-proportional hazards regression was applied. There were 673 CV deaths of which 432 were from CHD. Concentrations of apoB [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.09-3.61], apoA-I (HR 0.48, 95% CI 0.27-0.85) and total cholesterol (TC) (HR 1.17, 95% CI 1.02-1.34) were significantly related to CHD death, whereas high density lipoprotein cholesterol (HDL-C) (HR 0.68, 95% CI 0.45-1.05) was borderline significant. Both the apoB/apoA-I ratio (HR 2.14, 95% CI 1.11-4.10) and the TC/HDL-C ratio (HR 1.10, 95% CI 1.04-1.16) were related to CHD death. Only apoB (HR 2.01, 95% CI 1.05-3.86) and the apoB/apoA-I ratio (HR 2.09, 95% CI 1.04-4.19) remained significantly associated with CHD death after adjusting for CV risk factors. CONCLUSION: In the US population, apolipoprotein measurements significantly predict CHD death, independently of conventional lipids and other CV risk factors (smoking, dyslipidaemia, hypertension, obesity, diabetes and C-reactive protein). Furthermore, the predictive ability of apoB alone to detect CHD death was better than any of the routine clinical lipid measurements. Inclusion of apolipoprotein measurements in future clinical guidelines should not be discarded.

IGF-I/IGFBP-3 ratio: a mechanistic insight into the metabolic syndrome.

Recent reports suggest that IGF (insulin-like growth factor)-I and IGFBP-3 (IGF-binding protein-3) have independent and opposing mechanistic effects on insulin. The aim of the present study was to assess the relationship between the IGF-I/IGFBP-3 ratio and the metabolic syndrome. We examined 3281 subjects (1463 men and 1818 women, aged 20-49 years), otherwise healthy adults, who participated in NHANES III (Third National Health and Nutrition Examination Survey), which has released measurements of IGF-I and IGFBP-3. Insulin resistance was estimated using the computer HOMA2 (homoeostatic model assessment 2) model. The updated ATP-III (Adult Treatment Panel III) definition of the metabolic syndrome was used. We applied adjusted logistic and linear regression models. After adjusting for age and race, men and women in the lowest quartile of the IGF-I/IGFBP-3 ratio were 3-fold more likely to meet the ATP-III definition of the metabolic syndrome and twice as likely to be insulin-resistant. Mean values of the IGF-I/IGFBP-3 ratio decreased significantly as the number of metabolic syndrome components increased (P<0.0001, as determined by ANOVA). The area under the ROC (receiver operating characteristic) curve for detecting insulin resistance using the IGF-I/IGFBP-3 ratio was 0.760, significantly improving upon either protein alone (P=0.01). In conclusion, the IGF-I/IGFBP-3 ratio is significantly associated with the metabolic syndrome. Calculating the ratio of these two proteins may provide insight into the metabolic syndrome clustering phenomenon.

Beneficial effects of individualized physical activity on prescription on body composition and cardiometabolic risk factors: results from a randomized controlled trial.

BACKGROUND: Insufficient physical activity (PA), overweight and abdominal obesity are increasing global public health problems. DESIGN: Randomized controlled 6-month intervention study. METHODS: One hundred and one 68-year-old individuals (57% female) with low PA, overweight (BMI 25-40 kg/m) and abdominal obesity (waist circumference >88 cm in women and >102 cm in men), were randomized to PA on prescription (PAP) or a minimal intervention. PA measured by several methods, anthropometric parameters, body composition and cardiometabolic risk factors were measured at baseline and after intervention. RESULTS: Favourable changes in anthropometrics, body composition, S-glucose, glycosolated haemoglobin (HbA1c), blood lipids and apolipoproteins were seen in the PAP group. In the control group, however, some positive changes were also noted. Bodyweight, neck circumference, fat mass, S-cholesterol and HbA1c decreased significantly more in the PAP group. CONCLUSION: Individualized PAP improves body composition and cardiometabolic risk factors in sedentary older overweight individuals. PAP might be useful in clinical practice to counteract the epidemic of sedentary lifestyle and concomitant cardiometabolic disorders.

Leptin, a novel predictor of lung function in heart failure.

BACKGROUND: Leptin is a protein hormone produced by adipose tissue. Leptin has proinflammatory properties and is usually elevated in patients with chronic heart failure. We assessed if serum leptin relates to the loss in lung function in noncachectic patients with chronic heart failure. MATERIALS AND METHODS: One hundred thirty-five consecutively eligible non-Hispanic white subjects (age, 24 to 79 years; 85 men and 50 women) with a diagnosis of stable systolic heart failure were recruited prospectively, along with 106 matched control subjects. FVC, FEV(1), and single-breath diffusing capacity of the lung for carbon monoxide (DLco) were measured by spirometry. Plasma leptin was measured by radioimmunoassay. Multiple linear regression was applied. RESULTS: The relationships of FEV(1), FVC, and DLco with leptin differed significantly between heart failure and control subjects after controlling for age, sex, percentage of body fat, and ejection fraction. In heart failure, leptin was as an independent predictor of FVC values (additional R(2) = 0.05, p < 0.0001), FEV(1) values (additional R(2) = 0.05, p < 0.0001), and DLco values (additional R(2) = 0.14, p < 0.0001). In a final multiple regression model predicting lung function in heart failure, the independent effect of leptin was significant after further adjustments. CONCLUSIONS: The predictive information provided by leptin is additive to that provided by measures of body fat in heart failure patients, especially for DLco. Leptin may play a role in the impairment of lung function in subjects with heart failure.

Relation of increased leptin concentrations to history of myocardial infarction and stroke in the United States population.

Leptin, an adipose tissue-derived hormone, has been linked to cardiovascular outcomes; however, data are limited in the United States population, especially women. To assess the association between leptin concentrations and history of myocardial infarction (MI) and stroke independently of traditional cardiovascular risk factors, we analyzed data from 6,239 subjects (mean age 47 years; 3,336 women) with measurements of serum leptin and full assessment of cardiovascular risk factors from the National Health and Nutrition Examination Survey (NHANES) III. Logistic regression was used to estimate the cross-sectional association of leptin concentrations (highest quartile versus lowest quartile) and history of MI, stroke, and the composite end point of MI or stroke (MI/stroke). Gender-specific models of leptin were adjusted for age, race, dyslipidemia, hypertension, diabetes, smoking, and obesity status. There were 212 men with MI/stroke (5.4%), 154 with MI (4.1%), and 82 with stroke (1.7%). There were 135 women with MI/stroke (2.6%), 74 with MI (1.5%), and 78 with stroke (1.4%). In multivariate analysis, high leptin level was significantly and independently associated with MI/stroke in men (odds ratio [OR] 2.41, 95% confidence interval [CI] 1.20 to 4.93) and women (OR 4.26, 95% CI 1.75 to 10.73); with MI in men (OR 3.16, 95% CI 1.40 to 7.37) and women (OR 3.96, 95% CI 1.29 to 12.72), and with stroke in women (OR 3.20, 95% CI 1.04 to 10.54) but not in men (OR 1.37, 95% CI 0.38 to 3.88). In conclusion, in the United States population, increased leptin concentrations are significantly associated with MI/stroke in men and women independently of traditional cardiovascular risk factors and obesity status.

Decreased right and left ventricular myocardial performance in obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) may predispose patients to congestive heart failure (CHF), suggesting a deleterious effect of OSA on myocardial contractility. METHODS: A cross-sectional study of 85 subjects with suspected OSA who had undergone their first overnight polysomnogram, accompanied by an echocardiographic study. Patients were divided according to the apnea-hypopnea index as follows: < 5 (control subjects); 5 to 14 (mild OSA); and >or= 15 (moderate-to-severe OSA). Right and left ventricular function was evaluated using the myocardial performance index (MPI) and other echocardiographic parameters. For the right ventricle analyses, we excluded patients with a Doppler pulmonary systolic pressure of >or= 45 mm Hg, while for the left ventricle we excluded patients with an ejection fraction of

Correspondence between the adult treatment panel III criteria for metabolic syndrome and insulin resistance.

OBJECTIVE: The aim of the present study was to assess the diagnostic accuracy of the Adult Treatment Panel III (ATP-III) definition of the metabolic syndrome in identifying insulin-resistant individuals and to explore alternative approaches to improve identification of insulin-resistant individuals among asymptomatic adults from the general population. RESEARCH DESIGN AND METHODS: The sample consisted of 256 non-Hispanic white subjects without treated hypertension or diabetes, from the Rochester (Minnesota) Heart Family Study (123 men and 133 women; aged 20-60 years). Frequently sampled intravenous glucose tolerance tests were performed in all subjects. The reference standard for insulin resistance was determined by Bergman's minimal model; insulin resistance was defined as an insulin sensitivity index <2 x 10 min(-1) . microU(-1) . ml(-1). Component metabolic syndrome measures included blood pressure determined by sphygmomanometer; fasting serum triglycerides, HDL cholesterol, and glucose concentrations determined enzymatically; and waist circumference determined by tape measure. RESULTS: By ATP-III criteria, the prevalence of metabolic syndrome was 15.6% (16.3% in men and 15.1% in women; P = 0.465). The presence of metabolic syndrome had low sensitivity to identify insulin resistance (45% in men and 39% in women; sex difference, P = 0.137) but high specificity (93% in men and 95% in women; sex difference, P = 0.345). Based on the area under the receiver operating characteristic curve (AUC) constructed by counting metabolic syndrome components as recommended by ATP-III, diagnostic accuracy was fair (AUC = 0.797 in men and 0.747 in women). When component metabolic syndrome measures were considered as quantitative traits rather than dichotomized, use of waist circumference alone, rather than counting metabolic syndrome components, improved diagnostic accuracy for insulin resistance (in men, AUC = 0.906, P = 0.001; in women, AUC = 0.822, P = 0.10). CONCLUSIONS: Application of the ATP-III metabolic syndrome criteria provides good specificity but low sensitivity to screen asymptomatic white adults for insulin resistance. Measuring just waist circumference is simpler and may provide greater accuracy for identifying insulin resistance.

Comparison of apolipoprotein-B/apolipoprotein-AI in subjects with versus without the metabolic syndrome.

Recent studies have suggested that the apolipoprotein-B (apo-B)/apolipoprotein-AI (apo-AI) ratio predicts cardiovascular risk better than any of the cholesterol indexes. The aim of the present study was to assess if the apo-B/apo-AI ratio is related to the metabolic syndrome and its components. Data were analyzed from 2,964 subjects (mean age 48 years; 1,516 men, 1,448 women) from the National Health and Nutrition Examination Survey III with apolipoprotein data who were evaluated for the metabolic syndrome and its components. The metabolic syndrome was defined according to the criteria of the National Cholesterol Education Program Adult Treatment Panel III and the International Diabetes Federation. The mean values of the apo-B/apo-AI ratio in subjects with and without the metabolic syndrome were compared. Overall, the median distribution of the apo-B/apo-AI ratio was significantly greater (p <0.0001) in subjects with the Adult Treatment Panel III metabolic syndrome (0.90) than without (0.69). The apo-B/apo-AI ratio was associated significantly with each of the metabolic syndrome components, in descending order of magnitude: low high-density lipoprotein cholesterol (odds ratio [OR] 5.7), high triglycerides (OR 4.7), high waist circumference (OR 2.6), high fasting glucose (OR 1.9), and high blood pressure (OR 1.5). The apo-B/apo-AI ratio was also different between subjects with and without the metabolic syndrome. Mean values of apo-B/apo-AI increased significantly as the numbers of metabolic syndrome components increased in men (p <0.0001) and women (p <0.0001). After excluding high-density lipoprotein cholesterol and triglycerides as criteria for the metabolic syndrome, the association between means persisted (analysis of variance p <0.0001) in men and women. Apo-B/apo-AI was significantly associated with the presence of the metabolic syndrome (OR 5.1, p <0.0001). In conclusion, the apo-B/apo-AI ratio is strongly associated with the presence of individual metabolic syndrome components, with the metabolic syndrome itself, and with insulin resistance. An elevated apo-B/apo-AI ratio may constitute an important feature of the metabolic syndrome and may provide an additional mechanism to explain the increased cardiovascular risk in subjects with this syndrome.

Update in prevention of atherosclerotic heart disease: management of major cardiovascular risk factors.

Cardiovascular disease (CVD) remains as the first cause of death worldwide. Scientific community works everyday trying to ameliorate this burden. Only in the year 2004 around 2,790 publications about the therapeutic use of antihypertensive agents can be found in MEDLINE. Despite this overwhelming effort and information, only a relatively short number of manuscripts have a real impact in clinical practice. For the busy clinician, it becomes almost impossible to screen and be updated with the landmark publications. The purpose of this article is to provide concise information related to prevention of CVD. We reviewed publications in the past 5 years regarding cardiovascular risk factors with special attention to dyslipidemia, hypertension, diabetes, smoking cessation and obesity, discussing some new findings and treatments. We also discuss obstructive sleep apnea (OSA) as a recently identified cardiovascular risk factor, and provide a general overview about its pathophysiology and treatment.

Relation of body mass index to fatal and nonfatal cardiovascular events after cardiac rehabilitation.

The aim of the present study was to determine whether body mass index (BMI) influences survival and recurrent cardiovascular events in a cardiac rehabilitation population. We followed 389 consecutive entrants to cardiac rehabilitation for 6.4 +/- 1.8 years. Patients were stratified into 3 groups: normal (BMI 18 to 24.9 kg/m(2)), overweight (BMI 25 to 29.9 kg/m(2)), and obese (BMI > or =30 kg/m(2)). Total and cardiovascular mortality were inversely associated with BMI category in bivariate models. However, only cardiovascular mortality was significant after adjustment for age and gender (p < 0.044), with cardiovascular death rates of 10% in normal, 8% in overweight, and 2% in obese patients. The rates of nonfatal recurrent events were 10% in normal, 24% in overweight, and 25% in obese patients. Our data indicate that BMI is inversely related to cardiovascular mortality but positively related to the risk of nonfatal recurrent events.

[Epidemiological and clinical outlook of chronic Chagas' heart disease in Mexico]. / Panorama epidemiológico y clínico de la cardiopatía chagásica crónica en México.

OBJECTIVE: To compare the epidemiological and clinical characteristics of chronic Chagas' heart disease to other dilated cardiomyopathies. METHODS: A study comprising 128 patients from a heart disease center was carried out from 1993 to 2003. Of them, 51 (40%) were Trypasonoma cruzi positive. Epidemiological data was obtained through interviews and clinical and serological data from health services. Statistic analysis was conducted using the Chi-square, Fischer, Mann-Whitney or Students' t-test as well as multivariate analysis. RESULTS: Chronic Chagas' disease patients were older (55+/-10 years old) than those patients with cardiopathy (42+/-17 years old). Most of them were born in rural areas (90% vs 68%), lived in poor (75% vs 16%), crowded households (45% vs 20%), together with domestic animals (71% vs 61%) and were aware of the Chagas' vector (73% vs 25%). Rhythm and conduction ECG abnormalities as well as permanent pacemaker were common among Chagas' patients (84% vs 55%, 78% vs 64% and 24% vs 10%, respectively). Congestive heart failure was more frequent among cardiomiopathy patients (88% vs 71%). Both groups had abnormal myocardial perfusion with normal epicardial arteries. Comorbidities were more frequent in cardiomiopathy patients than in chronic Chagas' disease patient (two cases only). CONCLUSIONS: Chagas' disease is the most common cause of dilated cardiomiopathy in the study hospital. Due to its regional distribution in Mexico, it deserves special attention and control programs proven to be effective in other countries.

Facial fat and its relationship to abdominal fat: a marker for insulin resistance?

Reports of relationships between measures of insulin sensitivity and measures of body fat and fat distribution suggest that abdominal fat accumulation is a predictor of insulin resistance. It has been previously suggested that facial fat (primarily in the cheeks and neck) is strongly associated with visceral abdominal fat accumulation. The facial fat is a rich vascular region, that seems to be metabolically active and resembles abdominal white adipose tissue. We, therefore, hypothesize that facial fat could be a good predictor of insulin resistance. Whether facial fat can be used as an accurate marker for insulin resistance remains to be determined.