Development and implementation of an online clinical pathway for adult chronic kidney disease in primary care: a mixed methods study.

BACKGROUND: Primary care physicians and other primary health care professionals from Alberta, Canada identified a clinical pathway as a potential tool to facilitate uptake of clinical practice guidelines for the diagnosis, management and referral of adults with chronic kidney disease. We describe the development and implementation of a chronic kidney disease clinical pathway (CKD-CP; www.ckdpathway.ca ). METHODS: The CKD-CP was developed and implemented based on the principles of the Knowledge-To-Action Cycle framework. We used a mixed methods approach to identify the usability and feasibility of the CKD-CP. This included individual interviews, an online survey and website analytics, to gather data on barriers and facilitators to use, perceived usefulness and characteristics of users. Results are reported using conventional qualitative content analysis and descriptive statistics. RESULTS: Eighteen individual interviews were conducted with primary care physicians, nephrologists, pharmacists and nurse practitioners to identify themes reflecting both barriers and facilitators to integrating the CKD-CP into clinical practice. Themes identified included: communication, work efficiency and confidence. Of the 159 participants that completed the online survey, the majority (52 %) were first time CKD-CP users. Among those who had previously used the CKD-CP, 94 % agreed or strongly agreed that the pathway was user friendly, provided useful information and increased their knowledge and confidence in the care of patients with CKD. Between November 2014 and July 2015, the CKD-CP website had 10,710 visits, 67 % of which were new visitors. The 3 most frequently visited web pages were home, diagnose and medical management. Canada, Indonesia and the United States were the top 3 countries accessing the website during the 9 month period. CONCLUSIONS: An interactive, online, point-of-care tool for primary care providers can be developed and implemented to assist in the care of patients with CKD. Our findings are important for making refinements to the CKD -CP website via ongoing discussions with end-users and the development team, along with continued dissemination using multiple strategies.

Pharmacists on primary care teams: Effect on antihypertensive medication management in patients with type 2 diabetes.

OBJECTIVE: To identify which activities produced a significant improvement in blood pressure control in patients with type 2 diabetes when pharmacists were added to primary care teams. METHODS: This prespecified, secondary analysis evaluated medication management data from a randomized controlled trial. The primary outcome was a change in treatment, defined as addition, dosage increase, or switching of an antihypertensive medication during the 1-year study period. The secondary outcome was a change in antihypertensive medication adherence using the medication possession ratio (MPR). RESULTS: The 200 evaluable trial patients had a mean age of 59 (SD, 11) years, 44% were men, and mean blood pressure was 130 (SD, 16)/74 (SD, 10) mm Hg at baseline. Treatment changes occurred in 45 (42%) of 107 patients in the intervention group and 24 (26%) of 93 patients in the control group (RR, 1.63; 95% CI, 1.08-2.46). Addition of a new medication was the most common type of change, occurring in 34 (32%) patients in the intervention group and 17 (18%) patients in the control group (P = 0.029). Adherence to antihypertensive medication was high at baseline (MPR, 93%). Although medication adherence improved in the intervention group (MPR, 97%) and declined in the control group (MPR, 91%), the difference between groups was not significant (P = 0.21). CONCLUSION: The observed improvement in blood pressure control when pharmacists were added to primary care teams was likely achieved through antihypertensive treatment changes and not through improvements in antihypertensive medication adherence.

Adding pharmacists to primary care teams increases guideline-concordant antiplatelet use in patients with type 2 diabetes: results from a randomized trial.

BACKGROUND: Antiplatelet therapy is recommended as part of a strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. However, compliance with these guideline-recommended therapies appears to be less than ideal. OBJECTIVE: To assess the effect of adding pharmacists to primary care teams on initiation of guideline-concordant antiplatelet therapy in type 2 diabetic patients. METHODS: Prespecified secondary analysis of randomized trial data. In the main study, the pharmacist intervention included a complete medication history, limited physical examination, provision of guideline-concordant recommendations to the physician to optimize drug therapy, and 1-year follow-up. Controls received usual care without pharmacist interactions. Patients with an indication for antiplatelet therapy, but not using an antiplatelet drug at randomization were included in this substudy. The primary outcome was the proportion of patients using an antiplatelet drug at 1 year. RESULTS: At randomization, 257 of 260 study patients had guideline-concordant indications for antiplatelet therapy, but less than half (121; 47%) were using an antiplatelet drug. Overall, 136 patients met inclusion criteria for the substudy (71 intervention and 65 controls): 60% were women, with mean (SD) age 58.0 (11.9) years, diabetes duration 5.3 (6.0) years, and hemoglobin A(1c) 7.6% (1.5). Sixteen (12%) had established cardiovascular disease at enrollment. At 1 year, 43 (61%) intervention patients and 15 (23%) controls were using an antiplatelet drug (38% absolute difference; number needed to treat, 3; relative increase, 2.6; 95% CI 1.5-4.7; p < 0.001). Of these 58 patients, 52 (90%) were using aspirin 81 mg daily. CONCLUSIONS: Adding pharmacists to primary care teams significantly and substantially increased the proportion of type 2 diabetic patients using guideline-concordant antiplatelet therapy.

Influence of controlled rheumatoid arthritis on the action and disposition of verapamil: focus on infliximab.

Active rheumatoid arthritis (RA), obesity, and old age are associated with reduced responsiveness to the calcium channel antagonist verapamil despite increased drug concentrations. The diminishing effect appears to be associated with the severity of inflammation. We examined pharmacodynamics and pharmacokinetics of verapamil in patients with controlled RA. Volunteers included RA patients in remission: 12 on infliximab, 8 on other antirheumatic therapy, and 12 healthy subjects. Verapamil plasma concentrations and selected inflammatory mediators as well as blood pressure and electrocardiographic parameters were recorded after a single 80-mg dose of verapamil. Inflammatory mediators were all below what is reported for active RA, confirming that RA was controlled. The tumor necrosis factor-alpha concentration, however, was significantly higher in the infliximab group compared with other groups and the literature value for active RA. No significant difference was observed between groups in terms of percentage prolongation of PR interval despite a trend toward a lower response in the RA groups, the mean plasma concentrations, and the total and unbound area under the curve of verapamil. However, the slope of the S-verapamil concentration-effect curve was steeper for controls compared with the RA patients. Remission from active disease appears to restore plasma protein levels and hepatic drug metabolism activity in patients with RA, resulting in relatively normal verapamil pharmacokinetics.

DreamTel; Diabetes risk evaluation and management tele-monitoring study protocol.

BACKGROUND: The rising prevalence of type 2 diabetes underlines the importance of secondary strategies for the prevention of target organ damage. While access to diabetes education centers and diabetes intensification management has been shown to improve blood glucose control, these services are not available to all that require them, particularly in rural and northern areas. The provision of these services through the Home Care team is an advance that can overcome these barriers. Transfer of blood glucose data electronically from the home to the health care provider may improve diabetes management. METHODS AND DESIGN: The study population will consist of patients with type 2 diabetes with uncontrolled A1c levels living on reserve in the Battlefords region of Saskatchewan, Canada. This pilot study will take place over three phases. In the first phase over three months the impact of the introduction of the Bluetooth enabled glucose monitor will be assessed. In the second phase over three months, the development of guidelines based treatment algorithms for diabetes intensification will be completed. In the third phase lasting 18 months, study subjects will have diabetes intensification according to the algorithms developed. DISCUSSION: The first phase will determine if the use of the Bluetooth enabled blood glucose devices which can transmit results electronically will lead to changes in A1c levels. It will also determine the feasibility of recruiting subjects to use this technology. The rest of the Diabetes Risk Evaluation and Management Tele-monitoring (DreamTel) study will determine if the delivery of a diabetes intensification management program by the Home Care team supported by the Bluetooth enabled glucose meters leads to improvements in diabetes management. TRIAL REGISTRATION: Protocol NCT00325624.

A novel, non-invasive 13C-glucose breath test to estimate insulin resistance in obese prepubertal children.

Insulin resistance (IR) is an important risk factor for the development of type 2 diabetes mellitus in obese boys and girls. Because needle-associated fear and anxiety are common in children, non-invasive methods to determine IR are desirable. Our objective in this cross-sectional study of obese prepubertal children (n = 39) was to compare estimates of IR using a novel, non-invasive technique (13C-glucose breath test) with common indices of IR derived from an oral glucose tolerance test (OGTT). For the 13C-glucose breath test, samples were collected before and 90 minutes after ingestion of 25 mg 13C-labelled glucose. For the OGTT, glucose and insulin samples were collected at 0, 15, 30, 45, 60, 90 and 120 minutes. The homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), insulin area-under-the-curve (AUC), and sum-of-insulin were calculated as indices of IR. Pearson correlations revealed significant, but moderate, associations between the 13C-glucose breath test and fasting insulin (r = -0.50; p < 0.01), 2-hour insulin (r = plots showed acceptable levels of agreement between indices of IR. In obese prepubertal children, the 13C-glucose breath test can provide a proxy estimate of IR when gold-standard techniques are either unavailable or impractical.

The relationship between weight gain and blood pressure in children and adolescents.

BACKGROUND: The aim of this study was to determine the relationship between the trajectories of weight gain and systolic blood pressure (SBP) in youth. METHODS: Annual surveys of anthropometry, fitness, SBP, and its determinants (cardiac output, systemic vascular resistance, and arterial compliance) were conducted in youth (aged 5 to 19 years) in a school-based setting between 2004 and 2006. Children were stratified according to change in body mass index (BMI) over time. RESULTS: Within the entire cohort (n = 2089), mean SBP (121 +/- 16 SD v 112 +/- 15 SD mm Hg; P < .01) and the prevalence of high blood pressure (48% v 18%, P < .01) were significantly higher and fitness levels were lower (P < .01) in obese children, relative to healthy-weight peers. After 2 years of follow-up, despite similar SBP and BMI at baseline, the average change in SBP was approximately 4.5-fold greater in children with the largest increase in BMI, relative to children who experienced minimal weight gain. This group also experienced a significantly greater increase in stroke volume (P < .05), while the change in heart rate, arterial compliance, and systemic vascular resistance was comparable with that of children who experienced minimal weight gain. Multiple linear regression analysis revealed that SBP increased 0.77 mm Hg for every kilogram of weight gain over a period of 2 years (P < .01). CONCLUSIONS: Overweight and disproportionate weight gain in children are associated with elevated SBP. These data support the need for interventions to prevent excessive weight gain and obesity in children and adolescents.

The 2007 Canadian Hypertension Education Program recommendations for the management of hypertension: part 2 - therapy.

OBJECTIVE: To provide updated, evidence-based recommendations for the prevention and management of hypertension in adults. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence was reviewed from randomized controlled trials and systematic reviews of trials. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. For treatment of patients with kidney disease, the progression of kidney dysfunction was also accepted as a clinically relevant primary outcome. EVIDENCE: A Cochrane collaboration librarian conducted an independent MEDLINE search from 2005 to August 2006 to update the 2006 Canadian Hypertension Education Program recommendations. In addition, reference lists were scanned and experts were contacted to identify additional published studies. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS: Dietary lifestyle modifications for prevention of hypertension, in addition to a well-balanced diet, include a dietary sodium intake of less than 100 mmol/day. In hypertensive patients, the dietary sodium intake should be limited to 65 mmol/day to 100 mmol/day. Other lifestyle modifications for both normotensive and hypertensive patients include: performing 30 min to 60 min of aerobic exercise four to seven days per week; maintaining a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm in men and less than 88 cm in women); limiting alcohol consumption to no more than 14 units per week in men or nine units per week in women; following a diet reduced in saturated fat and cholesterol, and one that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and considering stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should take into account each individual's global atherosclerotic risk, target organ damage and any comorbid conditions: blood pressure should be lowered to lower than 140/90 mmHg in all patients and lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients require more than one agent to achieve these blood pressure targets. In adults without compelling indications for other agents, initial therapy should include thiazide diuretics; other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin-converting enzyme (ACE) inhibitors (except in black patients), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). First-line therapy for isolated systolic hypertension includes long-acting dihydropyridine CCBs or ARBs. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction, or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor plus diuretic combination is preferred; in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered. VALIDATION: All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Effect of a vitamin and mineral supplementation on glycemic status: Results from a community-based program.

AIMS: Diet is a major risk factor for type 2 diabetes mellitus. As cofactors necessary for enzyme function of all metabolic pathways, vitamins and minerals have the potential to improve glucose metabolism. We investigated the effects of a nutrient intervention program on glycemic status. METHODS: We used a form of natural experiment to compare Pure North program participants (n = 1018) that received vitamin D alone (Vital 1) or vitamin D in combination with other nutrients (Vital 2) during two different time periods. Changes in 25-hydroxyvitamin D [25(OH)D], high-sensitivity C reactive protein (hs-CRP), glycated hemoglobin (HbA1c) and glycemic status were characterized over one and two years. RESULTS: Serum 25(OH)D concentrations increased significantly in both Vital 1 (to 111  ±â€¯â€¯49 nmol/L) and Vital 2 (to 119  ±â€¯â€¯52 nmol/L) over one year. HbA1c and hs-CRP were significantly reduced over time in Vital 2. Higher 25(OH)D levels after one year were associated with larger decreases in HbA1c and hs-CRP in Vital 2. At one year, 8% of Vital 2 and 16% of Vital 1 participants progressed from normoglycemia to prediabetes/diabetes, whereas 44% of Vital 2 and 8% of Vital prediabetes/diabetes subjects regressed to normoglycemia. CONCLUSIONS: Vitamin D combined with other nutrients was associated with a reduced risk of progression to diabetes and with an increased rate of reversion to normoglycemia in high risk participants. The results suggest that nutrient supplementation regimes may provide a safe, economical and effective means for lowering diabetes risk. Further examination of this potential via randomized controlled trials is warranted.

Impaired arterial compliance and aerobic endurance in kidney transplant recipients.

BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplant recipients (KTR). Two risk factors for cardiovascular disease that have not been examined in this population are arterial compliance and aerobic capacity. The primary objective was to determine small and large artery compliance and aerobic endurance in KTR. A secondary objective was to explore the relationship between aging and arterial compliance and aerobic endurance in KTR. METHODS: Sixty-two clinically stable KTR were recruited from the University of Alberta Renal Transplant Clinic. Small and large artery compliance was assessed using computerized arterial pulse waveform analysis. Aerobic endurance was determined using the six-minute walk test. Age-matched normative data from healthy individuals was used for comparison. RESULTS: Small arterial compliance was lower in KTR (5.5+/-3 ml/mm Hg x 100) compared to age-matched healthy individuals' predicted values (7.9+/-0.9 ml/mm Hg x 100, P<0.0001). No difference was found for large artery compliance between KTR (16.0+/-6.6 ml/mm Hg x 10) and age-matched healthy predicted values (15.2+/-1.3 ml/mm Hg x 10, P=0.5). Small and large artery compliance were 35% (P=0.026) and 36% (P=0.005) higher in younger (<51 years) versus older (>51 years) KTR, respectively. The six-minute walk distance was 28% lower in KTR (495+/-92 m) compared to healthy age-predicted values (692+/-56 m P<0.0001). CONCLUSIONS: Compromised arterial compliance and poor aerobic endurance may partially explain the high incidence of cardiovascular disease in KTR. Interventions demonstrated to improve these parameters may afford substantial clinical benefit in this population.

Sedentary lifestyle and antecedents of cardiovascular disease in young adults.

BACKGROUND: The aim of this study was to determine whether sedentary young individuals are characterized by reductions in determinants of vascular health and insulin sensitivity relative to their physically active, age-matched peers. METHODS: A total of 135 otherwise healthy young men (n = 68) and women (n = 67) <40 years of age (28 +/- 5 years) were studied in this investigation and stratified into three groups based on physical activity status: 1) sedentary (n = 73); 2) physically active (n = 24); and 3) endurance-trained (n = 38). Arterial compliance and flow-mediated dilation were determined by diastolic pulse contour wave analysis and echocardiographic imaging of the brachial artery respectively. Insulin sensitivity was estimated from the homeostasis model for insulin resistance and the 13C-glucose breath test. RESULTS: Both conduit (16.4 +/- 0.5 v 19.5 +/- 0.7 mL/mmHg x 10; P < .01) and resistant (8.5 +/- 0.3 v 10.7 +/- 0.5 mL/mmHg x 100; P < .01) artery compliance were significantly lower in sedentary subjects than in physically active or endurance-trained subjects, whereas flow-mediated dilation was not different between the groups. The HOMA(IR) was 2.5-fold higher in the sedentary group than in the endurance-trained group (P < .05). CONCLUSIONS: Sedentary individuals are characterized by reductions in both arterial compliance and insulin sensitivity relative to their endurance-trained peers, independent of changes in conventional risk factors for cardiovascular disease. These findings lend further support for the need for regular physical activity in the prevention of cardiovascular disease in individuals of all ages.

Drug-disease interactions: losartan effect is not downregulated by rheumatoid arthritis.

Inflammatory conditions, such as rheumatoid arthritis, reduce response to calcium channel and beta-adrenergic antagonists but not the angiotensin II type 1 receptor (AT(1)R) antagonist valsartan. Inflammation also reduces clearance of some drugs or active metabolite, thereby reducing response. Active (n = 14) and controlled rheumatoid arthritis (n = 12) and healthy subjects (n = 12) received losartan (100 mg). Blood pressures were measured, and samples were taken for pharmacokinetic and inflammatory mediator concentration determination. Active disease significantly increased arthritic index, nitric oxide, and Creactive protein. Although no between-group difference in plasma losartan concentration-time curves was observed, concentrations of the active metabolite, EXP 3174, were significantly reduced by arthritis. This, however, was not accompanied by reduced clinical response. One subject produced no detectable concentrations of EXP 3174 likely due to insufficient CYP2C9 activity. Despite reduced concentrations of the active metabolite, AT1R antagonists potency does not appear to be reduced by inflammation.

The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: Part II - Therapy.

OBJECTIVE: To provide updated, evidence-based recommendations for the management of hypertension in adults. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence from randomized, controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. For lifestyle interventions, blood pressure (BP) lowering was accepted as a primary outcome given the lack of long-term morbidity/mortality data in this field. For treatment of patients with kidney disease, the development of proteinuria or worsening of kidney function was also accepted as a clinically relevant primary outcome. EVIDENCE: MEDLINE searches were conducted from November 2004 to October 2005 to update the 2005 recommendations. In addition, reference lists were scanned and experts were contacted to identify additional published studies. All relevant articles were reviewed and appraised independently by content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS: Lifestyle modifications to prevent and/or treat hypertension include the following: perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 standard drinks per week in men or nine standard drinks per week in women; follow a diet that is reduced in saturated fat and cholesterol and that emphasizes fruits, vegetables and low-fat dairy products; restrict salt intake; and consider stress management in selected individuals. Treatment thresholds and targets should take into account each individual's global atherosclerotic risk, target organ damage and comorbid conditions. BP should be lowered to less than 140/90 mmHg in all patients, and to less than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease (regardless of the degree of proteinuria). Most adults with hypertension require more than one agent to achieve these target BPs. For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic hypertension with or without systolic hypertension include beta-blockers (in those younger than 60 years), angiotensin-converting enzyme (ACE) inhibitors (in nonblack patients), long-acting calcium channel blockers or angiotensin receptor antagonists. Other agents for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine calcium channel blockers or angiotensin receptor antagonists. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with diabetes mellitus, ACE inhibitors or angiotensin receptor antagonists (or in patients without albuminuria, thiazides or dihydropyridine calcium channel blockers) are appropriate first-line therapies; and in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended. All hypertensive patients should have their fasting lipids screened, and those with dyslipidemia should be treated using the thresholds, targets and agents recommended by the Canadian Hypertension Education Program Working Group on the management of dyslipidemia and the prevention of cardiovascular disease. Selected patients with hypertension, but without dyslipidemia, should also receive statin therapy and/or acetylsalicylic acid therapy. VALIDATION: All recommendations were graded according to strength of the evidence and voted on by the 45 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Generalizability and persistence of a multifaceted intervention for improving quality of care for rural patients with type 2 diabetes.

OBJECTIVE: Most quality improvement efforts for type 2 diabetes have neglected cardiovascular risk factors and are limited by a lack of information about generalizability across settings or persistence of effect over time. RESEARCH DESIGN AND METHODS: We previously reported 6-month results of a controlled study of an intervention that improved cardiovascular risk factors for rural patients with type 2 diabetes. We subsequently provided the identical intervention to the control region after the main study was completed. The primary outcome was 10% improvement in systolic blood pressure, total cholesterol, or HbA(1c). We compared the previously reported 6-month effect of the original intervention with the effect of the crossed-over intervention to the former control region and remeasured outcomes in the original intervention region 12 months later. RESULTS: Our analysis included 200 original intervention and 181 crossed-over intervention subjects. The age of the population was 62.4 +/- 12.4 years (mean +/- SD), and 54.3% were women. A similar proportion of patients in the crossed-over intervention group achieved improvement in the primary composite outcome compared with the original intervention group (38 vs. 44%, respectively; P = 0.29). In adjusted analyses, we observed less improvement in blood pressure (adjusted odds ratio 0.40 [95% CI 0.17-0.75]) but greater improvements in total cholesterol (1.86 [0.93-3.7]) with the crossed-over intervention compared with the original intervention. We observed sustained improvements in total cholesterol and HbA(1c) levels in the original intervention group, whereas previous large gains in control of blood pressure diminished over time. CONCLUSIONS: We found that our intervention was generalizable across settings, and its effect persisted over time. Nevertheless, without ongoing intervention or reinforcement, we noted some loss of the original benefits that had accrued. Future translational work should incorporate interventions such as ours into ongoing systems of rural care.

Of the renin-angiotensin system and reactive oxygen species Type 2 diabetes and angiotensin II inhibition.

Rates of type 2 diabetes mellitus are increasing worldwide at an explosive rate. This "epidemic" is largely driven by a concomitant obesity epidemic, which is seen not only in affluent countries, but in industrializing countries as well, concomitant with the rapid change toward Western life-style patterns worldwide. Recent clinical trials such as Heart Outcomes Prevention Evaluation (HOPE), Losartan Intervention for Endpoint reduction (LIFE), and Study of Cognition and Prognosis in the Elderly (SCOPE) have indicated that blocking the renin-angiotensin system (RAS) may reduce the risk of developing type 2 diabetes mellitus. This effect may be explained by a variety of diabetogenic factors, which seem to be moderated by angiotensin II, such as free fatty acids (FFA) and the phenomena of adipocyte differentiation, as well as inflammation and oxidative damage. Insulin resistance, usually present in cases of impaired glucose tolerance, is the major identifiable defect in subjects at risk for type 2 diabetes. Elevated FFA levels result in reduced activation of phosphoinositol-3 kinase, an enzyme that is essential for normal insulin-stimulated glucose uptake. This reduction is potentiated by angiotensin II and consequently insulin-stimulated glucose uptake is improved by RAS inhibition. Furthermore, blockade of the angiotensin II AT(1)-receptor has been shown to stimulate the differentiation of adipocytes that store FFAs, which leads to reduced plasma FFA levels and decreased insulin resistance. There are also data suggesting that AT(1)-receptor blockade reduces inflammatory activation and the production of reactive oxygen species (ROS), a major factor in the pathophysiology of diabetes and a major cardiovascular risk factor. Both proinflammatory molecules and ROS increase the risk of insulin resistance and atherogenesis. It is thought that FFAs and hyperglycemia increase ROS production and oxidative stress, leading to the activation of signaling molecules such as nuclear factor kappa-B and other mediators of stress-sensitive pathways, which increases insulin resistance and will lead to beta-cell dysfunction and diabetic complications during the longer term. Inhibiting the RAS seems to have an effect on several steps in this cascade. There is an obvious need for large-scale clinical trials specifically designed to assess the protective benefits of blocking the RAS in individuals at risk of developing type 2 diabetes. Two such trials on the prevention of type 2 diabetes are ongoing, the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications (DREAM) study and the more ambitious Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, which is also assessing prevention of cardiovascular events.

The 2005 Canadian Hypertension Education Program recommendations for the management of hypertension: part II - therapy.

OBJECTIVE: To provide updated, evidence-based recommendations for the management of hypertension in adults. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence from randomized controlled trials and systematic reviews of trials was preferentially reviewed. While changes in cardiovascular morbidity and mortality were the primary outcomes of interest, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity/mortality data in this field, and for certain comorbid conditions, other relevant outcomes, such as development of proteinuria or worsening of kidney function, were considered. EVIDENCE: MEDLINE searches were conducted from November 2003 to October 2004 to update the 2004 recommendations. Reference lists were scanned, experts were contacted, and the personal files of the subgroup members and authors were used to identify additional published studies. All relevant articles were reviewed and appraised independently, using prespecified levels of evidence, by content and methodology experts. As per previous years, only studies that had been published in the peer-reviewed literature were included; evidence from abstracts, conference presentations and unpublished personal communications was not included. RECOMMENDATIONS: Lifestyle modifications to prevent and/or treat hypertension include the following: perform 30 min to 60 min of aerobic exercise on four to seven days of the week; maintain a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a reduced fat, low cholesterol diet with an adequate intake of potassium, magnesium and calcium; restrict salt intake; and consider stress management (in selected individuals). Treatment thresholds and targets should take into account each individual's global atherosclerotic risk, target organ damage and any comorbid conditions. Blood pressure should be lowered to 140/90 mmHg or less in all patients, and to 130/80 mmHg or less in those with diabetes mellitus or chronic kidney disease. Most adults with hypertension require more than one agent to achieve target blood pressures. For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic hypertension with or without systolic hypertension include beta-blockers (in those younger than 60 years), angiotensin-converting enzyme (ACE) inhibitors (except in black patients), long-acting calcium channel blockers and angiotensin receptor antagonists. Other agents appropriate for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine calcium channel blockers and angiotensin receptor antagonists. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with diabetes mellitus, ACE inhibitors or angiotensin receptor antagonists (or thiazides in patients with diabetes mellitus without albuminuria) are appropriate first-line therapies; and in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended. All hypertensive patients should have their fasting lipids screened, and those with dyslipidemia should be treated using the thresholds, targets and agents recommended by the Canadian Hypertension Education Program Working Group on the management of dyslipidemia and the prevention of cardiovascular disease. Selected patients with hypertension, but without dyslipidemia, should also receive statin therapy and/or acetylsalicylic acid therapy. VALIDATION: All recommendations were graded according to the strength of the evidence and voted on by the 43 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Comparison of the [13C]glucose breath test to the hyperinsulinemic-euglycemic clamp when determining insulin resistance.

OBJECTIVE: With increasing emphasis on the recognition of the metabolic syndrome and early type 2 diabetes, a clinically useful measure of insulin resistance is desirable. The purpose of this study was to evaluate whether an index of glucose metabolism, as measured by (13)CO(2) generation from ingested [(13)C]glucose, would correlate with indexes from the hyperinsulinemic-euglycemic clamp. RESEARCH DESIGN AND METHODS: A total of 26 subjects with varying degrees of insulin sensitivity underwent both the [(13)C]glucose breath test and the hyperinsulinemic-euglycemic clamp. Results from the [(13)C]glucose breath test were compared with measures of insulin sensitivity from the glucose clamp as well as with other commonly used indexes of insulin sensitivity. RESULTS: There was a strong correlation between the [(13)C]glucose breath test result and the glucose disposal rate (r = 0.69, P < 0.0001) and insulin sensitivity index (r = 0.69, P < 0.0001) from the insulin clamp. The magnitude of these correlations compared favorably with QUICKI and were superior to the homeostasis model assessment. CONCLUSIONS: The [(13)C]glucose breath test may provide a useful noninvasive assessment of insulin sensitivity.

Controlled trial of a multifaceted intervention for improving quality of care for rural patients with type 2 diabetes.

OBJECTIVE: Despite good evidence and clinical practice guidelines, studies document that treatment of type 2 diabetes is less than optimal. Lack of resources or limited access may put patients in rural communities at particular risk for suboptimal care. RESEARCH DESIGN AND METHODS: We conducted a prospective, before/after study with concurrent controls to assess the effectiveness of a multidisciplinary diabetes outreach service (intervention) for improving the quality of care for rural patients with type 2 diabetes. Our intervention consisted of six monthly visits by a traveling team of specialist physicians, nurses, dieticians, and a pharmacist. The core of this service was specialist-to-rural primary care physician academic group detailing. Two comparable regions in Northern Alberta were randomly allocated to control or intervention. Data were collected before and 6 months after intervention in a representative volunteer sample. The primary outcome was a 10% improvement in any one of the following: blood pressure, total cholesterol, or HbA(1c). RESULTS: Our analysis included 200 intervention and 179 control subjects; 14 subjects were at all three primary outcome targets at baseline. The intervention was associated with a trend toward improvement in primary outcome at 6 months (44% intervention vs. 37% control; odds ratio 1.32, 95% CI 0.87-1.99). The intervention was associated with a significant improvement in blood pressure (42% intervention vs. 25% control, P = 0.004); however, there were only small, nonsignificant changes in cholesterol or HbA(1c). The intervention was associated with a significant increase in satisfaction with diabetes care. Multivariate adjustment for baseline differences between intervention and control subjects did not affect any of the main results. CONCLUSIONS: A diabetes outreach service has the potential to improve the quality of diabetes care for rural patients. Future studies need to involve longer timelines and larger sample sizes.

Low cardiorespiratory fitness is associated with elevated C-reactive protein levels in women with type 2 diabetes.

OBJECTIVE: The purpose of this study was to examine differences in novel markers of cardiovascular disease (CVD) in women with type 2 diabetes stratified according to cardiorespiratory fitness. RESEARCH DESIGN AND METHODS: A total of 28 women (mean age 57 +/- 6 years) with type 2 diabetes who were free from overt CVD were placed into low cardiorespiratory fitness (LCF) or average cardiorespiratory fitness (ACF) groups based on a graded exercise test to exhaustion. A group of eight women without type 2 diabetes were also examined and served as healthy control subjects. The median VO(2peak) value was used as a cutoff for group determination. We assessed both conventional CVD risk factors, including blood pressure, BMI, and lipid profile, as well as novel CVD risk factors, such as left ventricular filling dynamics, arterial stiffness, fasting insulin, and C-reactive protein (CRP). RESULTS: VO(2peak) values were 69 +/- 14 and 91 +/- 24% of predicted values for sedentary age-matched healthy individuals in the LCF and ACF groups, respectively. BMI was significantly greater in the LCF group (P < 0.05); however, no differences were observed in age, lipid profile, or resting hemodynamics. CRP was 3.3-fold higher in the LCF group (6.3 +/- 41. vs. 1.9 +/- 1.7 mg/l, P < 0.05), whereas other novel markers of CVD were not significantly different between the groups. Significant negative relationships were observed between VO(2peak) and both CRP (r = -0.49) and the homeostasis model assessment index (r = -0.48) (P < 0.05). CONCLUSIONS: The novel finding of this investigation is that low cardiorespiratory fitness is associated with elevated CRP and reduced fasting glucose control in women with type 2 diabetes.

Improvements in patient-reported outcomes associated with an intervention to enhance quality of care for rural patients with type 2 diabetes: results of a controlled trial.

OBJECTIVE: The aim of this study was to examine patient-reported outcomes in a controlled trial of a multifaceted provider-level intervention to improve quality of care for rural patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a before/after intervention study with concurrent controls in two rural regions in Alberta, Canada. The intervention consisted of six monthly visits by a multidisciplinary health care team and was primarily directed at primary care providers. Clinical and patient-reported outcomes were assessed after 6 months. Patient-reported outcomes included changes in health-related quality of life (Health Utilities Index Mark 3 [HUI3]), satisfaction with care, lifestyle (Diabetes Lifestyle Form), and adherence to self-care activities. Analysis of covariance was used to assess differences over time between the control and intervention regions. RESULTS: A total of 200 intervention and 172 control subjects were included in this analysis. After adjusting for important clinical and demographic differences, a statistically significant and clinically important improvement in the overall HUI3 score was seen at the 6-month follow-up in the intervention region (0.06 [95% CI 0.02-0.10]) compared with the control region (0.01 [-0.04 to 0.04]) (P = 0.03 for the difference between groups). Satisfaction with general medical care (P < 0.001 between groups) and diabetes care (P < 0.001 between groups) increased among patients in the intervention region compared with the control region. Self-efficacy, attitudes, and beliefs about diabetes control all increased in the intervention region when compared with the control region, but adherence to self-care activities did not. CONCLUSIONS: A provider-level intervention directed at improving quality of clinical care for patients with type 2 diabetes also had a favorable impact on overall health-related quality of life, satisfaction with care, and other humanistic outcomes.