The long-term effect of intentional weight loss on changes in bone mineral density in persons with type 2 diabetes: results from the Look AHEAD randomized trial.

Intentional weight loss has been shown to increase bone loss short term but the long-term effects are not known. Data from the Look AHEAD clinical trial shows that a long term intentional weight loss intervention was associated with greater bone loss at the hip in men. PURPOSE: Intentional weight loss has been shown to increase bone loss short term and increase frailty fracture risk, but the long-term effects on bone mineral density (BMD) are not known. METHODS: Data from a subgroup from the Look AHEAD (LA) multicenter, randomized clinical trial was used to evaluate whether a long term intentional weight loss intervention would increase bone loss. In a preplanned substudy, BMD was assessed at 5 of the 16 LA clinical centers using dual-energy X-ray absorptiometry at baseline, year 8, and the observational visit 12.6-16.3 years after randomization (year 12-16). RESULTS: At year 8, bone density loss (%) was greater in the Intensive Lifestyle Intervention (ILI) group compared with the control group (DSE) for the femoral neck (p = 0.0122) but this finding was not observed at the year 12-16 visit. In analyses stratified by gender, bone density loss (%) was greater at the total hip for men in the ILI group than the DSE group at both the year 8 and year 12-16 visits (year 8 p = 0.0263 and year 12-16 p = 0.0062). This finding was not observed among women. CONCLUSION: Long term intentional weight loss was associated with greater bone loss at the hip in men. These results taken with the previously published Look AHEAD data from the entire clinical trial showing increased frailty fracture risk with weight loss in the ILI group suggest that when intentional weight loss is planned, consideration of bone density preservation and fracture prevention strategies is warranted. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00017953. June 21, 2001.

History of Cardiovascular Disease, Intensive Lifestyle Intervention, and Cardiovascular Outcomes in the Look AHEAD Trial.

OBJECTIVE: To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02]). METHODS: This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes. RESULTS: Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group. CONCLUSIONS: Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design.

Urinary cross-linked carboxyterminal telopeptide, a bone resorption marker, decreases after vaso-occlusive crises in adults with sickle cell disease.

People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode. Thirty-one of the 52 adults enrolled in the study had paired urine samples for CTX-1 analysis. Urinary CTX-1, corrected for urine creatinine, significantly decreased from a mean of 3.45 µg/mmol during vaso-occlusive crises to 2.62 µg/mmol at recovery (p = 0.01). Thus, increased bone loss appears to correlate with acute vaso-occlusive crises in sickle cell disease. Our finding that urinary CTX-1 can be used to probe bone degradation in sickle cell disease provides an important new tool for diagnosing and monitoring response to therapy for people with sickle cell-related bone loss.

Changes in skeletal muscle and organ size after a weight-loss intervention in overweight and obese type 2 diabetic patients.

BACKGROUND: The effect of a weight-loss intervention on the masses of lean tissues and organs in humans is not well known. OBJECTIVE: We studied the effects of a diet and exercise weight-loss intervention on skeletal muscle (SM) mass and selected organs over 2 y using MRI in overweight adults with type 2 diabetes. DESIGN: Participants were 53 women and 39 men [mean ± SD: age 58 ± 7 y; body mass index (BMI; in kg/m2) 32 ± 3] enrolled in the Look AHEAD (Action for Health in Diabetes) trial and randomly assigned to an intensive lifestyle intervention (ILI) or diabetes support and education (DSE) on whom 2 y of data were collected. MRI-derived measurements of SM, heart, liver, kidney, spleen, and pancreas were acquired. RESULTS: Adjusted for baseline weight, height, age, sex, and ethnicity, the ILI group weighed (mean ± SE) 6.6 ± 0.7 kg less after 1 y and 5.2 ± 0.7 kg less after 2 y, whereas the DSE group did not change significantly (-0.4 ± 0.6 and -1.0 ± 0.7 kg after 1 and 2 y, respectively; P-interaction < 0.001). Total SM decreased in both groups during year 1 (-1.4 ± 0.2 kg; P < 0.001) with appendicular SM regained during year 2. Liver and spleen masses decreased in the ILI group (-0.12 ± 0.02 and -0.006 ± 0.003 kg, respectively) but were unchanged in the DSE group (0.00 ± 0.02 and 0.004 ± 0.003 kg, respectively). Kidney mass decreased by 0.013 ± 0.003 kg (P < 0.001) over 2 y in both groups. CONCLUSIONS: Decreases in liver (in Caucasians but not African Americans) and spleen were detected after a 6.2-kg weight reduction compared with a control group. SM and kidney mass decreased in both groups. Appendicular SM was regained during the second year whereas trunk SM was not. No evidence of a disproportionate loss of high-metabolic rate organs (heart, liver, kidney, spleen) compared with SM was found.

The Look AHEAD Trial: bone loss at 4-year follow-up in type 2 diabetes.

OBJECTIVE: To determine whether an intensive lifestyle intervention (ILI) designed to sustain weight loss and improve physical fitness in overweight or obese persons with type 2 diabetes was associated with bone loss after 4 years of follow-up. RESEARCH DESIGN AND METHODS: This randomized controlled trial of intensive weight loss compared an ILI with a diabetes support and education (DSE) group among 1,309 overweight or obese subjects. Bone mineral density was assessed at baseline and after 1 year and 4 years of intervention. RESULTS: ILI was effective in producing significant weight loss (5.3% vs. 1.8% in ILI and DSE, respectively; P < 0.01) and increased fitness (6.4% vs. -0.8%) at year 4. In men, ILI participants had a greater rate of bone loss during the first year (-1.66% vs. -0.09% per year in ILI and DSE, respectively). Differences between groups were diminished by one-half after 4 years (-0.88% vs. -0.05% per year in ILI and DSE, respectively) but remained significant (P < 0.01). The difference in rate of hip bone loss between groups over 4 years was related to increased weight loss in ILI. Among women, the rate of bone loss did not differ between ILI and DSE after 4 years. CONCLUSIONS: A 4-year weight loss intervention was significantly associated with a modest increase in bone loss at the hip in men but not in women.

Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial.

OBJECTIVE: To compare effects of combinations of standard and intensive treatment of glycemia and either blood pressure (BP) or lipids in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS: ACCORD enrolled 10,251 type 2 diabetes patients aged 40-79 years at high risk for cardiovascular disease (CVD) events. Participants were randomly assigned to hemoglobin A1c goals of <6.0% (<42 mmol/mol; intensive glycemia) or 7.0-7.9% (53-63 mmol/mol; standard glycemia) and then randomized a second time to either 1) systolic BP goals of <120 mmHg (intensive BP) or <140 mmHg (standard BP) or 2) simvastatin plus fenofibrate (intensive lipid) or simvastatin plus placebo (standard lipid). Proportional hazards models were used to assess combinations of treatment assignments on the composite primary (deaths due to CVD, nonfatal myocardial infarction [MI], and nonfatal stroke) and secondary outcomes. RESULTS: In the BP trial, risk of the primary outcome was lower in the groups intensively treated for glycemia (hazard ratio [HR] 0.67; 95% CI 0.50-0.91), BP (HR 0.74; 95% CI 0.55-1.00), or both (HR 0.71; 95% CI 0.52-0.96) compared with combined standard BP and glycemia treatment. For secondary outcomes, MI was significantly reduced by intensive glycemia treatment and stroke by intensive BP treatment; most other HRs were neutral or favored intensive treatment groups. In the lipid trial, the general pattern of results showed no evidence of benefit of intensive regimens (whether single or combined) compared with combined standard lipid and glycemia treatment. The mortality HR was 1.33 (95% CI 1.02-1.74) in the standard lipid/intensive glycemia group compared with the standard lipid/standard glycemia group. CONCLUSIONS: In the ACCORD BP trial, compared with combined standard treatment, intensive BP or intensive glycemia treatment alone improved major CVD outcomes, without additional benefit from combining the two. In the ACCORD lipid trial, neither intensive lipid nor glycemia treatment produced an overall benefit, but intensive glycemia treatment increased mortality.

Genetic modifiers of cardiorespiratory fitness response to lifestyle intervention.

PURPOSE: Numerous prospective studies indicate that improved cardiorespiratory fitness reduces type 2 diabetes risk and delays disease progression. We hypothesized that genetic variants modify fitness response to an intensive lifestyle intervention (ILI) in the Action for Health in Diabetes (Look AHEAD) randomized clinical trial, aimed to detect whether ILI will reduce cardiovascular events in overweight/obese subjects with type 2 diabetes compared with a standard of care. METHODS: Polymorphisms in established fitness genes and in all loci assayed on the Illumina CARe iSelect chip were examined as predictors of change in MET level, estimated using a treadmill test, in response to a 1-yr intervention in 3899 participants. RESULTS: We identified a significant signal in previously reported fitness-related gene RUNX1 that was associated with 1-yr METs response in ILI (0.19 ± 0.04 MET less improvement per minor allele copy; P = 1.9 × 10(-5)) and genotype-intervention interaction (P = 4.8 × 10(-3)). In the chipwide analysis, FKBP7 rs17225700 showed a significant association with ILI response among subjects not receiving beta-blocker medications (0.47 ± 0.09 METs less improvement; P = 5.3 × 10(-5)) and genotype-treatment interaction (P = 5.3 × 10(-7)). The Gene Relationships Among Implicated Loci pathway-based analysis identified connections between associated genes, including those influencing vascular tone, muscle contraction, cardiac energy substrate dynamics, and muscle protein synthesis. CONCLUSIONS: This is the first study to identify genetic variants associated with fitness responses to a randomized lifestyle intervention in overweight/obese diabetic individuals. RUNX1 and FKBP7, involved in erythropoesis and muscle protein synthesis, respectively, are related to change in cardiorespiratory fitness in response to exercise.

Readiness redefined: a behavioral task during screening predicted 1-year weight loss in the look AHEAD study.

OBJECTIVE: Predicting outcome in weight loss trials from baseline characteristics has proved difficult. Readiness to change is typically measured by self-report. METHODS: Performance of a behavioral task, completion of food records, from the screening period in the Look AHEAD study (n = 549 at four clinical centers) was assessed. Completeness of records was measured by the number of words and Arabic numerals (numbers) recorded per day, the number of eating episodes per day, and days per week where physical activity was noted. The primary outcome was weight loss at one year. RESULTS: In univariable analysis, both the number of words recorded and the number of numbers recorded were associated with greater weight loss. In multivariable analysis, individuals who recorded 20-26, 27-33, and ≥34 words per day lost 9.12%, 11.40%, and 12.08% of initial weight, compared to 8.98% for individuals who recorded less than 20 words per day (P values of 0.87, 0.008, and <0.001, respectively, compared to <20 words per day). CONCLUSIONS: Participants who kept more detailed food records at screening lost more weight after 1 year than individuals who kept sparser records. The use of objective behavioral screening tools may improve the assessment of weight loss readiness.

Human cardiovascular disease IBC chip-wide association with weight loss and weight regain in the look AHEAD trial.

BACKGROUND/AIMS: The present study identified genetic predictors of weight change during behavioral weight loss treatment. METHODS: Participants were 3,899 overweight/obese individuals with type 2 diabetes from Look AHEAD, a randomized controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes. Analyses focused on associations of single nucleotide polymorphisms (SNPs) on the Illumina CARe iSelect (IBC) chip (minor allele frequency >5%; n = 31,959) with weight change at year 1 and year 4, and weight regain at year 4, among individuals who lost ≥ 3% at year 1. RESULTS: Two novel regions of significant chip-wide association with year-1 weight loss in ILI were identified (p < 2.96E-06). ABCB11 rs484066 was associated with 1.16 kg higher weight per minor allele at year 1, whereas TNFRSF11A, or RANK, rs17069904 was associated with 1.70 kg lower weight per allele at year 1. CONCLUSIONS: This study, the largest to date on genetic predictors of weight loss and regain, indicates that SNPs within ABCB11, related to bile salt transfer, and TNFRSF11A, implicated in adipose tissue physiology, predict the magnitude of weight loss during behavioral intervention. These results provide new insights into potential biological mechanisms and may ultimately inform weight loss treatment.

Longitudinal changes in dietary fat intake and associated changes in cardiovascular risk factors in adults with type 2 diabetes: the ACCORD trial.

AIMS: To measure dietary fat intake using the Puget Sound Eating Patterns (PEP) questionnaire, a validated 19-item food questionnaire, and to quantify how reduced dietary fat intake affects cardiovascular risk factors in adults with type 2 diabetes. METHODS: Randomized controlled trial including a subsample of 1781 Action to Control Cardiovascular Risk in Diabetes (ACCORD) participants. Participants received dietary counseling to consume a reduced-fat diet. Outcome measures included HbA1c, fasting lipid profile, blood pressure, and weight. Longitudinal linear regression analyses were used to evaluate relationships between baseline and follow-up PEP scores and cardiovascular risk factors. RESULTS: PEP scores decreased significantly from baseline to 12-month follow up with a mean difference of -0.09 ± 0.39, P<0.001. All of the fat intake subscales showed significant improvement at 12 months from baseline. White race, female gender, and more hours per week of physical activity were correlated with a decline in PEP scores at 1-year. A longitudinal decrease in dietary fat intake was associated with significantly less weight gain at 12- and 36-months and lower serum triglycerides at 1 year. CONCLUSIONS: Reduced fat intake as measured by a brief questionnaire was associated with significant improvement in some cardiovascular risk factors (triglycerides and weight), but not in others.

Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes.

UNLABELLED: Fructose consumption predicts increased hepatic fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Because of its ability to lower hepatic adenosine triphosphate (ATP) levels, habitual fructose consumption could result in more hepatic ATP depletion and impaired ATP recovery. The degree of ATP depletion after an intravenous (IV) fructose challenge test in low- versus high-fructose consumers was assessed. We evaluated diabetic adults enrolled in the Action for Health in Diabetes Fatty Liver Ancillary Study (n = 244) for whom dietary fructose consumption estimated by a 130-item food frequency questionnaire and hepatic ATP measured by phosphorus magnetic resonance spectroscopy and uric acid (UA) levels were performed (n = 105). In a subset of participants (n = 25), an IV fructose challenge was utilized to assess change in hepatic ATP content. The relationships between dietary fructose, UA, and hepatic ATP depletion at baseline and after IV fructose challenge were evaluated in low- (<15 g/day) versus high-fructose (≥ 15 g/day) consumers. High dietary fructose consumers had slightly lower baseline hepatic ATP levels and a greater absolute change in hepatic α-ATP/ inorganic phosphate (Pi) ratio (0.08 versus 0.03; P = 0.05) and γ-ATP /Pi ratio after an IV fructose challenge (0.03 versus 0.06; P = 0.06). Patients with high UA (≥ 5.5 mg/dL) showed a lower minimum liver ATP/Pi ratio postfructose challenge (4.5 versus 7.0; P = 0.04). CONCLUSIONS: High-fructose consumption depletes hepatic ATP and impairs recovery from ATP depletion after an IV fructose challenge. Subjects with high UA show a greater nadir in hepatic ATP in response to fructose. Both high dietary fructose intake and elevated UA level may predict more severe hepatic ATP depletion in response to fructose and hence may be risk factors for the development and progression of NAFLD.

Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy.

BACKGROUND: People with type 2 diabetes are at risk of cognitive impairment and brain atrophy. We aimed to compare the effects on cognitive function and brain volume of intensive versus standard glycaemic control. METHODS: The Memory in Diabetes (MIND) study was done in 52 clinical sites in North America as part of Action to Control Cardiovascular Risk in Diabetes (ACCORD), a double two-by-two factorial parallel group randomised trial. Participants (aged 55-80 years) with type 2 diabetes, high glycated haemoglobin A(1c) (HbA(1c)) concentrations (>7·5%; >58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive glycaemic control targeting HbA(1c) to less than 6·0% (42 mmol/mol) or a standard strategy targeting HbA(1c) to 7·0-7·9% (53-63 mmol/mol). Randomisation was via a centralised web-based system and treatment allocation was not masked from clinic staff or participants. We assessed our cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, at baseline and at 20 and 40 months. We assessed total brain volume (TBV), our primary brain structure outcome, with MRI at baseline and 40 months in a subset of participants. We included all participants with follow-up data in our primary analyses. In February, 2008, raised mortality risk led to the end of the intensive treatment and transition of those participants to standard treatment. We tested our cognitive function hypotheses with a mixed-effects model that incorporated information from both the 20 and 40 month outcome measures. We tested our MRI hypotheses with an ANCOVA model that included intracranial volume and factors used to stratify randomisation. This study is registered with ClinicalTrials.gov, number NCT00182910. FINDINGS: We consecutively enrolled 2977 patients (mean age 62·5 years; SD 5·8) who had been randomly assigned to treatment groups in the ACCORD study. Our primary cognitive analysis was of patients with a 20-month or 40-month DSST score: 1378 assigned to receive intensive treatment and 1416 assigned to receive standard treatment. Of the 614 patients with a baseline MRI, we included 230 assigned to receive intensive treatment and 273 assigned to receive standard treatment in our primary MRI analysis at 40 months. There was no significant treatment difference in mean 40-month DSST score (difference in mean 0·32, 95% CI -0·28 to 0·91; p=0·2997). The intensive-treatment group had a greater mean TBV than the standard-treatment group (4·62, 2·0 to 7·3; p=0·0007). INTERPRETATION: Although significant differences in TBV favoured the intensive treatment, cognitive outcomes were not different. Combined with the non-significant effects on other ACCORD outcomes, and increased mortality in participants in the intensive treatment group, our findings do not support the use of intensive therapy to reduce the adverse effects of diabetes on the brain in patients with similar characteristics to those of our participants. FUNDING: US National Institute on Aging and US National Heart, Lung, and Blood Institute.

Obesity and albuminuria among adults with type 2 diabetes: the Look AHEAD (Action for Health in Diabetes) Study.

OBJECTIVE: To determine the association between obesity measures and albuminuria in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: In the Look AHEAD (Action for Health in Diabetes) Study, BMI and waist circumference were measured among 4,985 participants while total percent body fat was measured by whole-body DEXA scans among 1,351 participants. Odds of albuminuria by quartiles of BMI, waist circumference, and percent total body fat were calculated using logistic regression analysis while adjusting for covariates. RESULTS: The highest quartile of BMI (odds ratio [OR] 1.72 [95% CI 1.40-2.11]) and waist circumference (OR 1.75 [95% CI 1.42-2.15]) was significantly associated with albuminuria compared with the lowest quartile after adjustment for covariates. No associations were noted between quartiles of percent total body fat and albuminuria in any model. CONCLUSIONS: Increased BMI and abdominal obesity are associated with albuminuria in overweight and obese adults with type 2 diabetes.

Personal healthcare worker (HCW) and work-site characteristics that affect HCWs' use of respiratory-infection control measures in ambulatory healthcare settings.

OBJECTIVES: To identify healthcare worker (HCW) and work-site characteristics associated with HCWs' reported use of recommended respiratory-infection control practices in primary and emergency care settings. DESIGN: A cross-sectional study using a self-administered questionnaire for HCWs during the summer and fall of 2005. SETTING: Primary and emergency care clinics at 5 medical centers in King County, Seattle, Washington. RESULTS: Nurse professionals who reported receiving training (odds ratio [OR], 2.5 [confidence interval {CI}, 1.1-5.9]; P=.029), instructional feedback from supervisors (OR, 3.0 [CI, 1.5-5.9]; P=.002), and management support for implementing safe work practices had a higher odds of also reporting adherence to recommended respiratory precautions, compared with nurses who did not. Training was the only important determinant for adherence to respiratory precaution measures among medical practitioners (OR, 5.5 [CI, 1.2-25.8]; P=.031). The reported rate of adherence to hand hygiene practices was higher among nurse professionals who were male (OR, 2.2 [CI, 1.0-4.9]; P=.045), had infants, small children, or older adults living at home (OR, 2.2 [CI, 1.2-3.9]; P=.007), reported cleanliness and orderliness of the establishment where they worked (OR, 2.0 [CI, 1.1-3.5]; P=.019), had received respiratory-infection control training (OR, 3.2 [CI, 1.8-6.0]; P<.001), and reported fears about catching a dangerous respiratory infection at work (OR, 2.3 [CI, 1.2-4.5]; P=.011). CONCLUSION: A number of HCW and work-site characteristics associated with HCWs' use of recommended respiratory-infection control measures have been identified. These potentially influential characteristics should be considered as targets or guides for further investigation, which should include the evaluation of intervention strategies.

Appraisal of recommended respiratory infection control practices in primary care and emergency department settings.

BACKGROUND: The severe acute respiratory syndrome (SARS) epidemic and concern about pandemic influenza prompted the Centers for Disease Control and Prevention (CDC) to develop guidelines to prevent the transmission of all respiratory infections in health care settings during first contact with a potentially infected person. The extent to which health care workers and institutions use these CDC recommended practices is uncertain. METHODS: The study examined health care worker adherence to CDC recommended respiratory infection control practices in primary care clinics and emergency departments of 5 medical centers in King County, Washington, using a self-administered questionnaire. All clinical, allied, and administrative health care workers in study settings were invited to participate: 653 (53%) responded, and 630 were included. RESULTS: The survey revealed important shortcomings in overall personal and institutional use of CDC recommended practices, including deficiencies in posted alerts, patient masking and separation, hand hygiene, personal protective equipment, staff training, and written procedures. Use of recommended measures was generally higher among nursing staff than medical practitioners. CONCLUSION: This study found significant gaps in adherence to CDC recommendations for the control of respiratory infections in ambulatory care clinical settings. Practical strategies are needed to identify and reduce barriers to implementation of recommended practices for control of respiratory infections.

Restricted-carbohydrate diets in patients with type 2 diabetes: a meta-analysis.

Many current popular weight-loss diets advocate restricting carbohydrates, but risks and benefits of these diets for patients with diabetes is unclear. We searched for articles published in English between 1980 and April 2006 regarding carbohydrate-restricted diets that included and reported separate results for adult, nonpregnant patients with type 2 diabetes. Articles were limited to studies completed in the United States and Canada. Available data on study design; carbohydrate composition of diet; duration of diet; and the outcomes of weight, lipid levels (total, low-density lipoprotein and high-density lipoprotein cholesterol, and triglycerides), hemoglobin A1c percent and/or fasting glucose were extracted. A total of 56 studies or reviews were evaluated. Thirteen studies met our inclusion criteria. Meta-regression analyses show that hemoglobin A1c, fasting glucose, and some lipid fractions (triglycerides) improved with lower carbohydrate-content diets. Overall effect on weight was equivocal among the studies evaluated in this meta-analysis. Randomized, controlled studies of restricted-carbohydrate diets in patients with diabetes need to be conducted in order to evaluate the overall sustainability of outcomes and long-term safety.

Evolution of the lipid trial protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial aims to test whether a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) plus a fibrate is more efficacious in reducing cardiovascular events than a statin plus placebo in patients with type 2 diabetes mellitus with defined glycemic control. This is a blinded component in a 5,518-patient subset of the ACCORD cohort. These participants were randomized to either be (1) treated with simvastatin (titrated to 40 mg/day if necessary to achieve a goal low-density lipoprotein [LDL] cholesterol level of <2.59 mmol/L [100 mg/dL]) plus placebo or (2) treated to the same goal LDL cholesterol level with the statin plus active fenofibrate 160 mg/day or its bioequivalent (or 54 mg/day if the estimated glomerular filtration rate ranges from 30 to <50 mL/min per 1.73 m2). Setting an upper limit of LDL cholesterol qualifying for randomization excluded patients who would not likely achieve the LDL cholesterol goal. Recruitment for ACCORD began in January 2001, and follow-up is scheduled to end in June 2009. Since recruitment began, several clinical trials and consensus statements have been published that led to changes in the details of the lipid treatment algorithm and protocol. This report describes the design of the lipid protocol and modifications to the protocol during the course of the study in response to and in anticipation of these developments. The current protocol is designed to provide an ethically justifiable test of combined statin plus fibrate treatment consistent with the highest level of safety and lipid treatment standards of care.

Regional histomorphology of cancellous bone in Macaca fascicularis.

The structural and dynamic characteristics of cancellous bone from biopsy sites representing different degrees of weight bearing were quantified following double fluorochrome labeling of adult male Macaca fascicularis. A strong correlation of bone formation rate was found between the humerus, tibia, and iliac crest within the same individual. There was no significant correlation between differing biopsy sites for the structural measures of bone. The coefficient of variation for bone formation rate at different sites from the same animal was comparable to the coefficient of variation for different animals measured at the same biopsy site. The present study suggests that any accessible site of cancellous bone will yield a representative measure of bone formation rate, but that structural measures are not generalizable between different sites. © 1996 Wiley-Liss, Inc.