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Non-communicable diseases (NCDs) have been on the rise in low- and middle-income countries (LMICs) over the last few decades and represent a significant healthcare concern. Over 85% of "premature" deaths worldwide due to NCDs occur in the LMICs. NCDs are an economic burden on these countries, increasing their healthcare expenditure. However, targeting NCDs in LMICs is challenging due to evolving health systems and an emphasis on acute illness. The major issues include limitations with universal health coverage, regulations, funding, distribution and availability of the healthcare workforce, and availability of health data. Experts from across the health sector in LMICs formed a Think Tank to understand and examine the issues, and to offer potential opportunities that may address the rising burden of NCDs in these countries. This review presents the evidence and posits pragmatic solutions to combat NCDs.

Noncommunicable diseases (NCDs) are responsible for 71% of all worldwide mortality each year, and have an exceptionally large impact in low- and middle-income countries (LMICs). However, there is often a lack of local data from these countries to inform practice and policy improvements. Generating locally contextualized evidence base for NCDs that can help identify gaps, aid decision-making and improve patient care in LMICs needs an innovative approach. The approach used in Mapping the Patient Journey Towards Actionable Beyond the Pill Solutions (MAPS) is designed to quantitatively map different stages of the patient journey in four critical NCDs, ie, hypertension, dyslipidemia, depression, and pain (chronic and neuropathic) across selected LMICs in Africa, the Middle East, South East Asia, and Latin America. The key touchpoints along the patient journey include awareness, screening, diagnosis, treatment, adherence, and control or remission. MAPS employs an evidence mapping methodology that follows a three-step semi-systematic review: 1) systematic peer-reviewed database search; 2) unstructured searches of local or real-world data; and 3) expert opinion. Evidence generation and visualization is based on locally validated and deduplicated data published over the last 10 years. This approach will be the first to provide quantitative mapping of the different stages of the patient journey for selected NCDs in LMICs. By focusing on local, patient-centric data, the goal of the MAPS initiative is to address and prioritize local research and knowledge gaps, then contribute to evidence-based, high-quality, and affordable advances in the management of NCDs in LMICs. This will ultimately improve patient outcomes and contribute towards the achievement of global NCD targets., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/IpYx9u1KTJk

Aims Noncommunicable diseases (NCD) cause 71% of all deaths worldwide. More than 85% of premature deaths (ages 30–69) occur in low- and middle-income countries (LMIC).] LMICs are not on target to achieve the United Nations’ Sustainable Develop Goals (UN SDG) 3.4. The aims were to create a multi-stakeholder forum to review NCD burden in LMICs; consider pragmatic solutions; and lead the conversation to inform the broader agenda on NCDs. Methods As key health stakeholders, medical leaders in Upjohn invited others to form an Expert Forum on NCDs in LMICs. These experts in clinical practice in primary and specialty care; academic research; patient advocacy; community pharmacy; public and health policy; civil society; mobile health; and private industry were chosen because they worked in LMICs; published peer-reviewed papers; committed to act together on NCDs. After an accelerated development sequence through storming, forming and norming, we commenced reviewing the NCD burden and challenges to overcome it. Through facilitated workshops, the team articulated how different sectors could, together, generate concepts for systemic solutions. Results The 19-member team has published a paper in a peer-reviewed journal that reviews the NCD-burden in LMICs; captures the rich workshop dialogue; presents the evidence and posits pragmatic solutions to combat the burden. Team members have further led the conversation through abstracts at international conferences and opinion editorials in key media, and communicated them via social media. Conclusions Private and public health sectors can indeed work together to lead the conversation on change. More partnerships may catalyse regional responses to address NCDs. On downstream efforts we included patients; a rewarding experience that embraced ‘nothing for us without us’. Next time, we would engage with government stakeholders and multilateral organisations. No one can afford to be a bystander; but we cannot do it alone.

Non-communicable diseases (NCDs) have been on the rise in low- and middle-income countries (LMICs) over the last few decades and represent a significant healthcare concern. Over 85% of “premature” deaths worldwide due to NCDs occur in the LMICs. NCDs are an economic burden on these countries, increasing their healthcare expenditure. However, targeting NCDs in LMICs is challenging due to evolving health systems and an emphasis on acute illness. The major issues include limitations with universal health coverage, regulations, funding, distribution and availability of the healthcare workforce, and availability of health data. Experts from across the health sector in LMICs formed a Think Tank to understand and examine the issues, and to offer potential opportunities that may address the rising burden of NCDs in these countries. This review presents the evidence and posits pragmatic solutions to combat NCDs., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/eB0JOLAYTPs

Hypertensive patients, such as those with established coronary artery disease (CAD) or those who have suffered a stroke, are at increased risk of morbidity and mortality. This systematic literature review and meta-analysis assesses the long-term effects of calcium channel blockers (CCBs) compared with other classes of antihypertensive medications on major cardiovascular (CV) outcomes in these high-risk subgroups of hypertensive patients. Randomized, active controlled parallel group trials were included if they compared CCBs with α-blockers, β-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, or diuretics, had a follow-up of ≥6 months, and had assessments of blood pressure (BP) and CV events [all-cause death, CV death, major CV events (myocardial infarction, MI; congestive heart failure, CHF; stroke; and CV death), MI, stroke, or CHF] in patients with baseline systolic/diastolic BP ≥140/≥90 mm Hg with either concomitant previous stroke and/or CAD. The final dataset included 19 publications reporting on 7 unique trials. In hypertensive patients with previous stroke, there was no difference between CCBs and comparators for any CV outcome. In those with CAD, there was no difference for all-cause death, CV death, major CV events, and MI for CCBs relative to comparators; however, a reduction in the risk of stroke and an increase in the risk of CHF were seen. For BP lowering, CCBs were at least as efficacious as comparators. The findings of our systematic review and analysis add to the body of evidence for the use of CCBs for the long-term treatment of hypertension in difficult-to-treat high CV risk populations.

Background Evidence suggests that patients with higher blood pressure variability ( BPV ) have a higher risk for stroke, but any link between BPV and stroke recurrence is unknown among those who had a stroke or transient ischemic attack ( TIA ). Methods and Results Data for patients with a history of stroke or TIA at enrollment were extracted from the ASCOT (Anglo Scandinavian Cardiac Outcomes Trial) and the ALLHAT (Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial). BPV was defined as the within‐subject standard deviation or coefficient of variation of systolic blood pressure across visits from 12 weeks poststroke or TIA onward. BPV was significantly higher in patients with a history of stroke or TIA than those without. BPV was a predictor of recurrent stroke in the pooled analysis. In the ASCOT study, 252 patients (12.3%) had a recurrent stroke among 2046 with a history of stroke. Incidence of recurrent stroke was significantly higher in the highest BPV quartile (17.8%) compared with the lowest quartile (10.5%); by treatment arm, this reached significance for the amlodipine‐arm only (high‐ BPV : 18.7% versus low‐ BPV : 12.9%; P =0.029). Of the 2173 patients from the ALLHAT with a history of stroke or TIA , patients with the highest quartile of BPV had a higher incidence of recurrent stroke (9.6%) compared with the lowest quartile BPV (5.5%); by treatment arm, this reached significance for the chlorthalidone‐arm only (high‐ BPV : 12.1% versus low‐ BPV : 5.4%; P =0.007). Conclusions Visit‐to‐visit BPV is a predictor of recurrent stroke in patients with a history of stroke or TIA on antihypertensive treatment. Considering BPV following a stroke may be important to reduce the risk for a recurrent stroke.

This post hoc analysis of CAMELOT and PREVENT analyzed the impact of blood pressure variability (BPV, assessed as within-subject standard deviation of SBP from 12 weeks onward) on the incidence of major adverse cardiovascular events (MACE, defined according to original studies). Patients (n = 1677 CAMELOT; n = 776 PREVENT) were stratified by BPV quartile. Regardless of study, BPV was significantly lower for amlodipine versus other treatments. In CAMELOT, a significant association between BPV quartile and MACE was observed with amlodipine treatment. Significant associations between BPV quartile and MACE were observed for both studies, when analyzed overall (adjusting for treatment). In CAMELOT, with amlodipine treatment, an increased risk for MACE was observed with high (BPV ≥ Q3) versus low BPV (< Q1; adjusting for characteristics and risk factors). In both studies, increased risk for MACE was observed for BPV ≥ Q3 versus BPV

The long-term cardiovascular (CV) effects of calcium channel blockers, with special focus on amlodipine, were compared with other classes of antihypertensive medications in high-risk hypertensive patient subgroups. A systematic literature review and meta-analysis was undertaken of 38 unique randomized, active-controlled, parallel-group trials comparing amlodipine/calcium channel blockers with diuretics, β-blockers, α-blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers, with ≥6-month follow-up, and which had included assessment of blood pressure (BP) and CV events [all-cause death, CV death, myocardial infarction (MI), stroke, congestive heart failure (CHF), or major CV events (MACE: MI, CHF, stroke, and CV death)], in hypertensive patients (baseline systolic/diastolic BP ≥140/≥90 mm Hg) with either concomitant diabetes and/or renal dysfunction. In hypertensive patients with diabetes, no difference was found for amlodipine versus comparators with respect to all-cause death, CV death, MACE, and MI; a decrease in stroke risk, and an increase in CHF risk, was seen. In hypertensive patients with renal dysfunction, no difference was found for amlodipine versus comparators with respect to all-cause death, CV death, MACE, MI, and CHF; a decrease in stroke risk was seen. Amlodipine was found to be at least as efficacious as all the other classes of antihypertensive agents in reducing systolic and diastolic BP. Long-term control of BP is critical for avoiding complications of hypertension in high-risk patients, particularly CV and cerebrovascular events such as stroke. This analysis has provided evidence that amlodipine is an appealing therapeutic option in the long-term management of hypertension in both diabetic and renal dysfunction patients.

Blood pressure (BP) is monitored and managed to prevent cardiovascular complications of hypertension, but BP variability (BPV) has not been sufficiently studied. This analysis assessed whether patients receiving amlodipine vs other antihypertensive agents had lower BPV after ≥12 weeks of treatment. Studies were included if individual subject data were available, had ≥1 active comparator, and treatment duration was ≥12 weeks. BPV was assessed using standard deviation (SD) and coefficient of variation (CV) of systolic BP across visits from 12 weeks. Individual trial and meta-analyses were performed for SD- and CV-based methodology. Five studies (47,558 BPV-evaluable patients) were included. Patient characteristics were largely consistent across the studies, but BP measurements varied from ∼4 months to ∼6 years. BPV with amlodipine was significantly (P .0001) lower vs atenolol and lisinopril; significantly (P .0001) lower than enalapril in one study and numerically, but not significantly lower in another; and similar to chlorthalidone and losartan. Meta-analysis revealed a treatment difference (standard error) for amlodipine vs all active comparators of -1.23 (0.46; P = .008) mm Hg using SD and -0.86 (0.31; P = .005) using CV. These findings suggest that amlodipine is effective for minimizing BPV. Future studies need to confirm a causal link between BPV and cerebrovascular/cardiovascular outcomes.

Background Sildenafil citrate is indicated for the treatment of erectile dysfunction. An orally disintegrating tablet (ODT) of sildenafil citrate has been developed for the benefit of patients who have difficulty swallowing solid dosage forms. Objective The main goal of this study was to evaluate the bioequivalence of sildenafil ODT with and without water versus marketed sildenafil oral film-coated tablets. A secondary objective was to evaluate the effects of a high-fat meal on the pharmacokinetics of sildenafil ODT. Methods The bioequivalence study of sildenafil ODT given with and without water versus marketed sildenafil citrate film-coated oral tablets was conducted in 36 subjects. In a food-effect study, the effect of a standard high-fat meal on the pharmacokinetics of sildenafil ODT was evaluated in 12 subjects. Both studies were randomized, open-label, crossover, single-dose (50 mg) studies in healthy men aged ≥45 years. Plasma samples were collected for 14 hours postdose, and pharmacokinetics were determined by using noncompartmental analyses. Results All subjects in both studies were Asian males between the ages of 45 and 69 years. Sildenafil ODT without water was bioequivalent to the marketed sildenafil film-coated oral tablet as the 90% CI for the ratio of geometric means of C max , AUC 0–∞ , and AUC 0–last were contained within equivalence limits (80%–125%). When sildenafil ODTs were given with water, the 90% CIs for sildenafil AUC 0–∞ and AUC 0–last were contained within the range of 80% to 125%; however, the 90% CI for sildenafil C max was not (79.76–92.78). This difference in C max is unlikely to have any clinically meaningful impact. High-fat meals reduced the rate but not the extent of absorption of sildenafil. Mean C max was reduced by 59%, and median T max was delayed from 0.625 hour (fasting) to 4 hours (high-fat meal). However, AUC values were comparable between fed and fasted treatments. Conclusions Sildenafil ODT, given with or without water, provides equivalent systemic exposure compared with marketed sildenafil film-coated oral tablets, thus offering a convenient alternative method of administration. Considering the results of the food-effect study, sildenafil ODT should be taken on an empty stomach. ClinicalTrials.gov identifiers: NCT01254383 (bioequivalence) and NCT01254396 (food effect).

Objectives This study was designed to determine the predictive value of lipid hydroperoxide (LOOH) levels for adverse cardiovascular outcomes in patients with stable coronary artery disease (CAD). Background Oxidative modification of circulating lipids contributes to inflammation and endothelial dysfunction, which are hallmark features of atherosclerosis. A serum biomarker of oxidation is LOOH, which is a primary product of fatty acid peroxidation. Methods Serum LOOH levels were measured and correlated with clinical events over a 3-year period in 634 patients with angiographic evidence of CAD. Results Baseline LOOH levels in the highest quartile were associated with hazard ratios of 3.24 (95% confidence interval [CI] 1.86 to 5.65; p = 0.0001) for nonfatal vascular events (n = 149), 1.80 (95% CI 1.13 to 2.88; p = 0.014) for major vascular procedures (n = 139), and 2.23 (95% CI 1.44 to 3.44; p = 0.0003) for all vascular events and procedures. Baseline LOOH levels correlated with serum levels of soluble intercellular adhesion molecule-1 (p = 0.001) and thiobarbituric acid reactive substances (p = 0.001) as well as the mean percent change in stenosis for large segments >50% stenosed (p = 0.048). A multivariate proportional hazards model, adjusted for traditional risk factors and inflammatory markers, showed an independent effect of LOOH on nonfatal vascular events, vascular procedures, and all events or procedures. Amlodipine treatment was associated with reduced cardiovascular events and changes in LOOH levels compared with placebo. Conclusions Elevated LOOH levels were predictive of nonfatal vascular events and procedures in patients with stable CAD, independent of traditional risk factors and inflammatory markers.

Objectives The objective of this study was to test the predictive value of an oxidative stress biomarker in 634 patients from the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT). Background Oxidative stress contributes to mechanisms of atherosclerosis and plaque instability. Biomarkers of oxidation, such as malondialdehyde (MDA), may represent independent indicators of risk for patients with stable coronary artery disease (CAD). Methods Serum MDA levels were measured as thiobarbituric acid reactive substances (TBARS) in 634 patients with documented CAD using reverse-phase high-performance liquid chromatography and spectrophotometric approaches. Results During the three-year study, there were 51 major vascular events such as fatal/nonfatal myocardial infarction, 149 hospitalizations for nonfatal vascular events, and 139 patients underwent a major vascular procedure. At baseline, patients with TBARS levels in the highest quartile had a relative risk (RR) of 3.30 (95% confidence interval [CI] 1.47 to 7.42; p = 0.038) for major vascular events, RR of 4.10 (95% CI 2.55 to 6.60; p Conclusions Serum levels of TBARS were strongly predictive of cardiovascular events in patients with stable CAD, independently of traditional risk factors and inflammatory markers.

Small reductions in blood pressure reduce the risk of cardiovascular events. Here, we report 2 post hoc pooled analyses assessing the antihypertensive effect of amlodipine in patients who had not responded to 5 mg and were uptitrated to 10 mg. The first analysis assessed subgroups of patients aged either younger than 55 years or 55 years or older and the second analysis pooled all patients irrespective of age. Of 706 patients in the age-related analysis, a statistically significant decrease in blood pressure from baseline was observed {for younger than 55 years [N = 253]: systolic blood pressure = −12.8 [standard error (SE) = 0.90] mm Hg, diastolic blood pressure = −8.0 [SE = 0.55] mm Hg; for 55 years or older [N = 453]: systolic blood pressure = −12.1 [SE = 0.66] mm Hg, diastolic blood pressure = −6.7 [SE = 0.39] mm Hg; all P < 0.0001}. In total, 45.8% and 39.3% of patients aged younger than 55 and 55 years or older, respectively, achieved their blood pressure goals. Adverse events were experienced by 62 (24.5%) patients aged younger than 55 years and 136 (30.0%) patients aged 55 years or older. Similar efficacy and safety results were seen in the all patient pooled analysis. Titration of amlodipine from 5 mg to 10 mg significantly decreased blood pressure in older hypertensive patients, which is clinically relevant because increased age is associated with hypertension and cardiovascular events.

Non—insulin-dependent diabetes mellitus (NIDDM) and hyperhomocysteinemia are both associated with premature vascular disease. We tested the hypothesis that homocysteine is associated with vascular disease and other diabetic complications in patients with NIDDM. The current investigation is a cross-sectional analysis of baseline variables for participants in the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial. Men and women aged 40 to 74 years with NIDDM and a mean diastolic blood pressure (BP) of 80 mm Hg or higher were eligible. We measured serum levels of total homocysteine (tHcy), cystathionine, and methylmalonic acid (MMA) and correlated these values with clinical and other laboratory measures of the complications of diabetes mellitus in 452 subjects. tHey was higher in males than in females and correlated with the duration of hypertension and systolic BP. tHcy was significantly correlated with MMA (r = .35, P < .0001) and cystathionine (r = .53, P < .0001) levels and inversely correlated with serum B12 (r = −.23, P < .0001) and folate (r = −.18, P < .0001). It was significantly correlated with serum creatinine (r = .28, P < .0001 for males and r = .39, P < .0001 for females) and inversely correlated with creatinine clearance (r = −.19, P < .005 for males and r = −.30, P < .0001 for females). tHcy was not increased in subjects with cardiovascular disease or retinopathy, but it was increased in those with neuropathy (10.3 v 9.3 μmol/L, P < .05) and macroalbuminuria (11.0 v 9.2 μmol/L, P < .005). Of these subjects, 2.2% met the criteria for vitamin B12 deficiency and 1% met the criteria for folate deficiency. We conclude that elevations of tHcy in this population appear to be the result of a combination of vitamin deficiency and decreased renal function and do not appear to be a predictor of cardiovascular disease.

Previous studies evaluating the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism have revealed that expression of the DD genotype is associated with an increase in myocardial infarction, cardiomyopathy, and left ventricular (LV) mass in nondiabetic patients. In the present study, a cross-sectional analysis was performed to evaluate the potential relationship between the ACE I/D genotypes and the LV mass index in 289 non–insulin-dependent diabetes mellitus (NIDDM) subjects without known coronary artery disease. Two dimensional directed M-mode echocardiograms along with selected patient characteristics were obtained from the study population. The distribution of the I/D polymorphism was as follows: 63 were II (22%), 137 were ID (47%), and 89 were DD (31%). Univariately, the DD genotype was associated with an increase in LV mass in men but not in women. When subjected to a multiple regression model that included age, systolic blood pressure, duration of diabetes, duration of hypertension, presence of the black race, and the presence of the DD genotype, the DD genotype was independently associated with an increase in the LV mass index with a parameter estimate of 10.5 g/m 2 (95% CI = 3.9, 17.0; P .002) in the male subjects. Thus, in this NIDDM study population, male patients with the DD genotype are independently associated with an increased LV mass.

Analysis of claims data from 46,076 diabetic patients without cardiovascular disease initiating atorvastatin or simvastatin therapy suggested that, after adjusting for demographic and clinical confounders, use of atorvastatin was associated with fewer cardiovascular events versus simvastatin at doses of similar potency (HR 0.88, 95% CI 0.80–0.97, P =0.01).

This study examines whether there was an association between smoking and nephropathy in patients with non-insulin-dependent diabetes mellitus enrolled in the Appropriate Blood Pressure Control in Diabetes Trial. Sixty-one percent of the patients were smokers; 26% had microalbuminuria, and 14% had overt nephropathy. There was a univariate association between diabetic nephropathy and gender, smoking status, duration of diabetes, hypertension, glycosylated hemoglobin level, creatinine level, body mass index, and cholesterol level. Stepwise logistic regression demonstrated an independent association between smoking and diabetic nephropathy (odds ratio 1. 61; 95% confidence interval 1.01, 2.58). These findings may have important implications for patients with non-insulin-dependent diabetes mellitus who smoke.

Non-insulin-dependent diabetes mellitus (NIDDM) occurs with a higher frequency in Hispanic as compared with non-Hispanic whites. It also appears that there is a higher prevalence of diabetic nephropathy in the Hispanic population when compared with non-Hispanic whites. In the current study, 144 Hispanics and 671 non-Hispanic white NIDDM subjects were studied to determine the possible association of various risk factors and diabetic complications, including overt albuminuria, with diabetic retinopathy. Stereoscopic retinal fundus photographs were obtained and graded by the University of Wisconsin Fundus Photographic Reading Center. We also sought to determine whether risk factors for retinopathy vary between Hispanics and non-Hispanic whites. In the total group, duration of diabetes, glycosylated hemoglobin, neuropathy, diastolic hypertension, use of insulin, and Hispanic ethnicity correlated with the presence of retinopathy. Controlling for severity and duration of diabetes, Hispanics had a significantly increased risk of retinopathy relative to non-Hispanic whites (OR = 2.13, 95% CI = 1.34, 3.37, P = 0.0013). Duration of diabetes and presence of neuropathy were significantly correlated with the presence of diabetic retinopathy in Hispanics and non-Hispanic whites. The presence of overt albuminuria (>200 microg/min), although not related to diabetic retinopathy in non-Hispanic whites, conferred a high risk for diabetic retinopathy in Hispanics (OR = 11.14, CI = 1.20, 103.39, P = 0.0339) independent of other risk factors. In summary, Hispanics with NIDDM have an increased prevalence of diabetic retinopathy when compared with non-Hispanic whites. In addition, overt albuminuria in the Hispanic subjects appears to be a powerful predictor of the diabetic retinopathy.

In conditions associated with insulin resistance, insulin-like growth factor binding protein-I (IGFBP-I) levels have been shown to correlate inversely with insulin levels. Puberty is associated with insulin resistance and thus provides a model for comparing the relationship of IGFBP-I to both insulin levels and measures of insulin sensitivity. Our study population consisted of 104 healthy pubertal children, age 9.8-14.6 yr. Each subject had his/her insulin sensitivity (Si) assessed by the modified minimal model of Bergman, which employs a frequently sampled i.v. glucose tolerance test. Results showed that IGFBP-I levels were significantly higher in boys than in pubertally matched girls (P < 0.01). There was a strong positive correlation between IGFBP-I levels and Si (r = 0.65, P < 0.0001) and a weaker negative correlation with fasting insulin levels (r = -0.38, P < 0.0001). An inverse relationship was also found between IGFBP-I levels and body mass index (r = -0.46, P < 0.0001) and with IGF-I levels (girls only, r = -0.41, P < 0.003). Consequently, insulin sensitivity, obesity, and IGF-I are important predictors of IGFBP-I levels in pubertal children. It is possible that insulin-mediated suppression of IGFBP-I in obese children may increase free IGF-I levels and thus contribute to somatic growth. The same mechanism may operate in pubertal children, where insulin resistance and growth acceleration occur simultaneously.

OBJECTIVE Exercise capacity has been used as a noninvasive parameter for predicting cardiovascular events. It has been demonstrated previously in NIDDM patients that several risk factors (i.e., obesity, smoking, hypertension, and African-American race) are associated with an impaired exercise capacity. We studied 265 male and 154 female NIDDM patients who underwent graded exercise testing with expired gas analyses to determine the possible influences of diabetic neuropathy, nephropathy, and retinopathy on exercise capacity. RESEARCH DESIGN AND METHODS Univariate and multiple linear regression analyses were performed to determine the relationship between diabetic neuropathy, urinary albumin excretion (UAE), and retinopathy with respect to peak oxygen consumption (Vo2). Neuropathy was assessed by neurological symptom and disability scores, autonomic function testing, and quantitative sensory exams involving thermal and vibratory sensation. Three categories of UAE were used: normal albuminuria (200 μg/min). Retinopathy was assessed by stereoscopic fundus photographs. Multiple linear regression analyses were then performed controlling for age, sex, length of diagnosed diabetes, duration of hypertension, race and ethnicity, GHb, BMI, and smoking to determine whether there was an independent effect of these diabetic complications on exercise capacity. RESULTS Univariate analyses revealed that the presence of diabetic retinopathy (P = 0.03), neuropathy (P = 0.002), microalbuminuria (P = 0.04), and overt albuminuria (P = 0.06) were associated with a lower peak Vo2. Multiple linear regression analyses were performed to determine independent relationships with peak Vo2. The results revealed that increasing retinopathy stage (Parameter estimate [PE] = −0.59 ± 0.3 ml · kg−1 · min−1; P = 0.026) and increasing UAE stage (PE = −0.62 ± 0.3 ml · kg−1 · min−1; P = 0.044) were associated with a decrease in peak Vo2. CONCLUSIONS In the present study of NIDDM subjects, a significant independent association was demonstrated between diabetic nephropathy and retinopathy with exercise capacity. These results were obtained controlling for age, sex, length of diagnosed diabetes, hypertension, race, and BMI. Thus the findings in this large NIDDM population without a history of coronary artery disease indicate a potential pathogenic relationship between microvascular disease and exercise capacity.

Identification of risk factors for development of diabetic sensorimotor peripheral neuropathy (DSPN) and diabetic autonomic neuropathy (DNA) may help to prevent or modify these complications. The ABCD Trial, a prospective study of diabetic complications, has identified risk factors of the presence and staging of peripheral neuropathy based on neurological symptom scores, neurological disability scores, autonomic function testing and quantitative sensory examination. DSPN is independently associated with diabetes duration [odds ratio (OR) = 1.5 per 10 years], body weight (OR = 1.1 per 5 kg), age (OR = 1.8 per 10 years), retinopathy (OR = 2.3), overt albuminuria (OR = 2.5), height (OR = 1.2 per 10 cm), duration of hypertension (OR = 1.1 per 10 years), insulin use (OR = 1.4), and race/ethnicity [African American vs. non-Hispanic white (OR = 0.4) and Hispanic vs. non-Hispanic white (OR = 0.8)]. DAN is independently associated with diabetes duration (OR = 1.2 per 10 years), body weight (OR = 1.1 per 5 kg), glycosylated hemoglobin (OR = 1.1 per 2.5%), overt albuminuria (OR = 1.6), and retinopathy (OR = 1.8).

Kazuomi Kario,1 Jeffery Robbins,2 Barrett W Jeffers21Division of Cardiovascular Medicine, Jichi Medical University, Shimotsuke, Japan; 2Pfizer, New York, NY, USAAbstract: In this retrospective analysis, data pooled from two Phase III/IV open-label Asian studies were used to quantify the additional blood pressure efficacy achieved when titrating amlodipine from 5 mg to 10 mg in mild/moderate hypertensive patients, and compared to data pooled from three Western studies. The primary efficacy end point was the change from baseline in sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) to the specified time point (4–8 weeks, depending on the trial). For the Asian analysis (n=174), both mean SBP and DBP were significantly decreased at the final visit (SBP -13.3 mmHg, 95% confidence interval [CI] -15.5 to -11.0; DBP -9.2 mmHg, 95% CI -10.6 to -7.8; both P

Aims To investigate the relationship between visit-to-visit blood pressure variability (BPV) and the progression of both carotid and coronary artery disease (CAD). Methods and results Data from two cardiovascular endpoint studies [Norvasc for Regression of Manifest Atherosclerotic Lesions by Intravascular Sonographic Evaluation (NORMALISE) and Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT)] were analysed separately. Systolic BPV was assessed as within-subject standard deviation of systolic BP across visits from 12-weeks onwards. Follow-up was 24 months (NORMALISE) or 36 months (PREVENT). Any association between BPV and progression of atherosclerosis was assessed using quantitative coronary angiography (QCA), intravascular ultrasound (IVUS), or B-mode ultrasound (depending on study). Patients from NORMALISE (n = 261) and PREVENT (n = 688 for QCA; n = 364 for ultrasound) were stratified within study according to median systolic BPV. No significant difference in change of minimal luminal diameter (by QCA in PREVENT) or change in percent atheroma volume or normalized total atheroma volume (by IVUS in NORMALISE) was detected for subjects with low BPV (BPV

Aims To investigate the relationship between visit-to-visit blood pressure variability (BPV) and the progression of both carotid and coronary artery disease (CAD). Methods and results Data from two cardiovascular endpoint studies [Norvasc for Regression of Manifest Atherosclerotic Lesions by Intravascular Sonographic Evaluation (NORMALISE) and Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT)] were analysed separately. Systolic BPV was assessed as within-subject standard deviation of systolic BP across visits from 12-weeks onwards. Follow-up was 24 months (NORMALISE) or 36 months (PREVENT). Any association between BPV and progression of atherosclerosis was assessed using quantitative coronary angiography (QCA), intravascular ultrasound (IVUS), or B-mode ultrasound (depending on study). Patients from NORMALISE (n = 261) and PREVENT (n = 688 for QCA; n = 364 for ultrasound) were stratified within study according to median systolic BPV. No significant difference in change of minimal luminal diameter (by QCA in PREVENT) or change in percent atheroma volume or normalized total atheroma volume (by IVUS in NORMALISE) was detected for subjects with low BPV (BPV

The objective of this study was to examine whether differences in effectiveness exist between statins in hypertensive patients seen in clinical practice. We assessed cardiovascular (CV) outcomes in hypertensive patients without cardiovascular disease who began therapy with atorvastatin (10 or 20 mg/d) or simvastatin (20 or 40 mg/d) between January 1, 2003, and September 30, 2005, using claims data from 92 US managed care plans in the PharMetrics database. A total of 98,471 hypertensive patients were identified, comprising 74,685 atorvastatin users (mean dose 13.6 mg/d) and 23,786 simvastatin users (mean dose 28.6 mg/d), and followed a median 1.5 years for the occurrence of a first CV event. The crude CV event rates were 2.81 and 3.92 per 100 person-years for atorvastatin and simvastatin, respectively [unadjusted hazard ratio (HR): 0.73; 95% confidence interval (CI): 0.68-0.78, P < 0.001]. After adjusting for clinical and demographic confounders, use of atorvastatin was associated with fewer CV events compared with simvastatin (HR: 0.91; 95% CI: 0.84-0.98, P = 0.009). However, the lipid-lowering efficacy of the 2 statins could not be assessed as patient lipid data were unavailable. In conclusion, hypertensive patients without cardiovascular disease who initiated atorvastatin (10 or 20 mg/d) had a significantly lower risk of subsequent CV events compared with those who initiated simvastatin at doses of similar potency (20 or 40 mg/d). As with all observational studies, the study is subject to certain limitations, and the findings should be regarded as hypothesis generating.

Insulin resistance is a known sequela of obesity; however, the relationship of insulin resistance to future weight gain remains unclear. In several studies, insulin resistance has been associated with weight stabilization. For the most part, this relationship has been found in adults who are overweight. To evaluate the relationship of insulin resistance to future fat accumulation in pubertal children, a 3-yr prospective study was carried out. Insulin sensitivity (Si) was determined by Bergman's minimal model in 111 healthy children, aged 9.7-14.5 yr. All children were Tanner stage II or III pubertal development at baseline. Body composition was assessed by body mass index, skinfold thickness, hydrodensitometry, and bioelectric impedance analysis at baseline and annually thereafter for an additional 3 yr. A repeated-measures analysis showed that the change in percentage body fat estimated from skinfold thickness [%BF(SF)] over time changed with increasing Si (P < 0.0001). Si was divided into tertiles for each gender, with the lowest tertile representing the most insulin-resistant children. For girls, those in the lowest tertile maintained their %BF(SF) over 3 yr, whereas those girls in the middle and upper tertile had an increase in their %BF(SF). For boys, those in the lowest tertile showed a decrease in their %BF(SF), whereas those boys in the middle and upper tertile maintained their %BF(SF). These results suggest that during puberty, children who are more insulin resistant have decreased sc fat gain.

Objective: To determine if hyperhomocysteinemia is a risk factor for the development of diabetic sensorimotor peripheral neuropathy (DSPN) and diabetic autonomic neuropathy (DAN). Background: Hyperhomocysteinemia and non-insulin-dependent diabetes mellitus (NIDDM) are both associated with premature vascular disease. Microvascular ischemia may be a risk factor for DSPN and DAN; therefore, the relationship of hyperhomocysteinemia to DSPN and DAN was investigated. Methods: Baseline neurological tests and homocysteine levels were determined in patients from a large prospective study of diabetic complications, the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial. Results: Total homocysteine (tHcy) was independently associated with DAN; for each 1 μmol/l increase in tHcy, there was a 7.1% increased risk of developing DAN (P

The purpose of this study was to determine oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ), and energy expenditure (EE) in a group of preterm ventilated infants during the first 3 weeks of life, and to determine the major factors that influence EE. Thirty-eight indirect calorimetry studies were performed in 18 ventilated infants with mean gestational age of 27.9 ± 0.6 (SEM) weeks. The relationship of demographic factors, nutrient intake, and severity of illness assessments on EE were determined by regression analysis. Repeated measure analysis was performed for the effect of multiple studies in the same patient. Although VO 2 , VCO 2 , and EE all tended to increase over the first 3 weeks of life, there was a wide range of values. EE was best predicted by nonprotein calorie intake and postnatal age, while there was no correlation with birthweight, weight at the time of study, gestational age, protein intake, or severity of illness. Multiple regression analyses demonstrated a strong interaction between PNA and EI. In this population EE is best predicted by PNA and El. The interactive effect between PNA and EI on EE is probably explained by the clinical practice of daily increments in substrate intake in these patients.

OBJECTIVE: Women with uncomplicated type 2 diabetes have both a decreased maximal oxygen consumption (VO2max) and slowed oxygen uptake (VO2) kinetics at the onset of exercise compared with nondiabetic women. These abnormalities are seen not only at maximal workloads, but also at the onset of low-level exercise. To evaluate the hypothesis that VO2max and VO2 kinetics would improve with exercise training in untrained people with type 2 diabetes, we measured these parameters in premenopausal sedentary women before and after 3 months of supervised exercise training. RESEARCH DESIGN AND METHODS: A total of 8 women with type 2 diabetes, 9 overweight nondiabetic women, and 10 lean nondiabetic women were studied. At baseline and after 3 months of exercise training, subjects underwent bicycle ergometer testing to obtain VO2max and VO2 kinetics data. RESULTS: On entry, women with type 2 diabetes had the lowest VO2max and slowest VO2 kinetics of the three groups. After exercise training, the women with type 2 diabetes improved their VO2max more than the lean and overweight control women: 28 vs. 5 and 8%, respectively (P < 0.05 for the diabetic group vs. both control groups). In the group with diabetes, VO2 kinetics improved by 39 and 22% at 20 and 30 W, respectively. For the control subjects, VO2 kinetics did not improve at any workload in either group. CONCLUSIONS: Despite beginning with the lowest VO2max and slowest VO2 kinetics, subjects with type 2 diabetes benefited more from an exercise training program than did control subjects. These findings suggest that in addition to its known metabolic effects, exercise training in individuals with type 2 diabetes may be an effective therapy to improve the cardiovascular response to exercise and to overcome low-level exercise impairment as reflected by improved VO2max and VO2 kinetics. If the ability to make circulatory adjustments at the beginning of exercise at low workloads is improved by an exercise training program, as suggested by the VO2 kinetics data, the clinical significance of exercise for people with type 2 diabetes is clear.

It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications. Because this issue remains controversial, we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were randomly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study.The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective, randomized, blinded trial comparing the effects of moderate control of blood pressure (target diastolic pressure, 80 to 89 mm Hg) with those of intensive control of blood pressure (diastolic pressure, 75 mm Hg) on the incidence and progression of complications of diabetes. The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes. In the current study, we analyzed data on a secondary end point (the incidence of myocardial infarction) in the subgroup of patients in the ABCD Trial who had hypertension.Analysis of the 470 patients in the trial who had hypertension (base-line diastolic blood pressure,or = 90 mm Hg) showed similar control of blood pressure, blood glucose and lipid concentrations, and smoking behavior in the nisoldipine group (237 patients) and the enalapril group (233 patients) throughout five years of follow-up. Using a multiple logistic-regression model with adjustment for cardiac risk factors, we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infarctions (a total of 24) than enalapril (total, 4) (risk ratio, 9.5; 95 percent confidence interval, 2.7 to 33.8).In this population of patients with diabetes and hypertension, we found a significantly higher incidence of fatal and nonfatal myocardial infarction among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril. Since our findings are based on a secondary end point, they will require confirmation.

Hypertension is a common comorbidity with non-insulin-dependent diabetes mellitus (NIDDM). Data are somewhat inconsistent as to whether hypertension exacerbates diabetic complications in this population. Therefore, we examined the relationship between hypertension and vascular complications of NIDDM in the 950 patients enrolled in the prospective and randomized Appropriate Blood Pressure Control in Diabetes (ABCD) study. We found both systolic and diastolic hypertension to be associated with diabetic nephropathy (P < .001) as well as with its macrovascular complications (P < .05). Our present results also demonstrated that there was a significant relationship between hypertension and peripheral vascular disease (P < .05), and left ventricular hypertrophy (P < .001). There was, however, no apparent relationship between hypertension and diabetic neuropathy. Thus, arterial pressure may be a major determinant of complications in NIDDM.

The ABCD (Appropriate Blood Pressure Control in Diabetes) Trial is a large, prospective, randomized clinical trial of 950 patients with non-insulin-dependent diabetes mellitus (NIDDM) designed to compare the effects of intensive blood pressure control with moderate control on the prevention and progression of diabetic nephropathy, retinopathy, cardiovascular disease, and neuropathy in NIDDM. The secondary objective is to determine equivalency of the effects of a calcium channel blocker (nisoldipine) and an angiotensin-converting-enzyme inhibitor (enalapril) as a first-line antihypertensive agent in the prevention and/or progression of these diabetic vascular complications. The study consists of two study populations aged 40–74 years, 470 hypertensive patients (diastolic blood pressure of ≥ 90.0 mmHg at time of randomization) and 480 normotensive patients (diastolic blood pressure of 80.0 mmHg at time of randomization). The study duration is 5 years and is scheduled to end in May of 1998. Patients are randomized to receive either intensive antihypertensive drug therapy or moderate antihypertensive drug therapy. Patients are also randomized to nisoldipine or enalapril, with open-label medications added if further blood pressure control is necessary. The primary outcome measure is glomerular filtration rate as assessed by 24-h creatinine clearance. Secondary outcome measures are urinary albumin excretion, left ventricular hypertrophy, retinopathy, and neuropathy. Cardiovascular morbidity and mortality will also be evaluated. Given the data showing the impact of hypertension on complications in NIDDM, the ABCD Trial is designed to determine if intensive antihypertensive therapy will be more efficacious than moderate antihypertensive therapy on the outcome of diabetic complications in NIDDM. [Diabetologia (1996) 39: 1646–1654]

OBJECTIVE The relationship between urinary albumin excretion (UAE) and diabetic complications in NIDDM has not been studied in a large American population. The demonstrated relationship between increased UAE and the development of retinopathy, nephropathy, and neuropathy in IDDM makes this an important issue to also be studied in NIDDM patients. RESEARCH DESIGN AND METHODS A large population study of 947 NIDDM patients living predominantly in a metropolitan area was undertaken. Three categories of UAE, namely, normal albuminuria (< 20 μg/min), microalbuminuria (20–200 μg/min), and overt albuminuria (>200 μg/min) were compared with 1) retinopathy as assessed by stereoscopic fundus photographs; 2) cardiovascular disease as assessed by a history of cardiac disease or stroke; ischemic changes on exercise treadmill testing; Q wave myocardial infarction; Estes, Sokolow, or Cornell criteria for left ventricular hypertrophy; positive Rose questionnaire for angina; and an abnormal Doppler exam for peripheral vascular disease; and 3) neuropathy as assessed by neurological symptom and disability scores, autonomic function testing, and quantitative sensory exams involving thermal and vibratory sensation. Selected patient characteristics were then evaluated to determine their effects on the presence of diabetic complications using univariate analyses. Multiple logistic regression analyses were then performed to determine the independent effect of UAE on these diabetic complications. RESULTS χ2 analyses revealed that UAE was significantly associated with the presence of retinopathy (P < 0.001), neuropathy (P < 0.001), and cardiovascular disease (P < 0.001). In the multiple logistic regression analyses, UAE had strong independent associations with retinopathy, neuropathy, and cardiovascular disease. CONCLUSIONS Thus, increasing UAE in this large NIDDM population in the U.S. was associated with an increased prevalence of diabetic retinopathy, neuropathy, and cardiovascular disease. This suggests that UAE may be more than an indicator of renal disease in NIDDM patients and, in fact, may reflect a state of generalized vascular damage occurring throughout the body. Prospective studies in NIDDM patients are needed to determine the predictive effect of UAE and the effect of decreasing UAE on future diabetic micro- and macrovascular complications.

Exercise capacity has been used as a noninvasive parameter for predicting cardiovascular events. It is known that diabetic patients have an impaired exercise capacity when compared with nondiabetic age-matched control subjects, but the risk factors associated with this impairment have not been thoroughly analyzed. A total of 453 male and female NIDDM patients who underwent graded exercise testing with expired gas analysis were studied to determine the possible influences of demographic and cardiac risk factors on exercise capacity. Univariate and multiple linear regression analyses were performed on baseline patient characteristics with respect to peak oxygen consumption (VO2). In the regression analyses, African-American race was strongly associated with a decrease in peak VO2; the difference in means between African-Americans and other subjects for men was −2.50 ml.kg−1 · min−1 (−4.28, −0.07, 95% CI) (P < 0.006) and for women was −2.96 ml.kg−1 · min−1 (−4.45, −1.47) (P < 0.0002). Univariate analyses revealed that African-American subjects had increased prevalence, longer duration, and higher systolic and diastolic hypertension than the non-Hispanic and Hispanic whites. Other independent predictors of peak VO2 (reported as change in peak VO2 in milliliters per kilogram per minute) were BMI (men: −0.39 kg/m2 [−0.52, −0.29], P < 0.0001; women: −0.39 kg/m2 [−0.48, −0.31], P < 0.0001), age (men: −0.16/year [−0.23, −0.09], P < 0.0001; women: −0.17/year [−0.24, −0.11], P < 0.0001), baseline resting systolic blood pressure (men: −0.03/mmHg [−0.06, −0.01], P < 0.05; women: −0.03/mmHg (−0.06, −0.01], P< 0.05), and pack-years smoking (men: −0.04/pack-years [−0.04, −0.01], P < 0.01; women: −0.04/pack-years [−0.07, −0.01], P < 0.0001). Thus, in this large NIDDM study, weight loss, smoking cessation, and aggressive blood pressure control, particularly in African-Americans with NIDDM, would appear to be important in improving exercise capacity and potentially improving the increased cardiovascular mortality associated with an impaired exercise capacity.