BACKGROUND We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy. METHODS In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. RESULTS At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P = 0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P = 0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29). CONCLUSIONS Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)

Background Persons with type 2 diabetes (T2D) are at risk for cognitive impairment and brain atrophy. The ACCORD Memory in Diabetes (MIND) Study investigated whether persons randomized to an intensive glycaemic therapeutic strategy targeting HbA1c to <6% had better cognitive function and a larger brain volume at 40 months than persons randomized to a standard strategy targeting HbA1c to 7%–7.9%. Methods ACCORD MIND was a double 2×2 factorial parallel group randomised trial conducted in 52 clinical sites in North America. Participants [age 55 – <80 years] with T2D, high HbA1c concentrations (>7.5%), and at high risk for cardiovascular events were randomised to treatment groups using a centralized web-based system. Clinic staff and participants were not blinded to treatment arm. The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 participants. All participants with follow-up data were included in the primary analyses. In February, 2008, increased mortality risk led to the termination of the intensive therapy and transition of those participants to standard glycaemic treatment. Results Randomised patients (n=2977; mean age 62.3 years) were consecutively enrolled; the final analysis included 1358 intensive and 1416 standard arm participants with a 20 or 40 month DSST score. Of the 614 with a baseline MRI, 230 intensive and 273 standard therapy participants were included in the analysis. There was no treatment difference in the DSST score. The intensive group had a greater TBV than the standard group (difference, 4.62; 95% CI 2.0 to7.3 cm3; p=0.0007). Interpretation Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND participants. (ClinicalTrials.gov number, NCT00182910).

IMPORTANCE Physical rehabilitation in the intensive care unit (ICU) may improve the outcomes of patients with acute respiratory failure. OBJECTIVE To compare standardized rehabilitation therapy (SRT) to usual ICU care in acute respiratory failure. DESIGN, SETTING, AND PARTICIPANTS Single-center, randomized clinical trial at Wake Forest Baptist Medical Center, North Carolina. Adult patients (mean age, 58 years; women, 55%) admitted to the ICU with acute respiratory failure requiring mechanical ventilation were randomized to SRT (n=150) or usual care (n=150) from October 2009 through May 2014 with 6-month follow-up. INTERVENTIONS Patients in the SRT group received daily therapy until hospital discharge, consisting of passive range of motion, physical therapy, and progressive resistance exercise. The usual care group received weekday physical therapy when ordered by the clinical team. For the SRT group, the median (interquartile range [IQR]) days of delivery of therapy were 8.0 (5.0–14.0) for passive range of motion, 5.0 (3.0–8.0) for physical therapy, and 3.0 (1.0–5.0) for progressive resistance exercise. The median days of delivery of physical therapy for the usual care group was 1.0 (IQR, 0.0–8.0). MAIN OUTCOMES AND MEASURES Both groups underwent assessor-blinded testing at ICU and hospital discharge and at 2, 4, and 6 months. The primary outcome was hospital length of stay (LOS). Secondary outcomes were ventilator days, ICU days, Short Physical Performance Battery (SPPB) score, 36-item Short-Form Health Surveys (SF-36) for physical and mental health and physical function scale score, Functional Performance Inventory (FPI) score, Mini-Mental State Examination (MMSE) score, and handgrip and handheld dynamometer strength. RESULTS Among 300 randomized patients, the median hospital LOS was 10 days (IQR, 6 to 17) for the SRT group and 10 days (IQR, 7 to 16) for the usual care group (median difference, 0 [95% CI, −1.5 to 3], P = .41). There was no difference in duration of ventilation or ICU care. There was no effect at 6 months for handgrip (difference, 2.0 kg [95% CI, −1.3 to 5.4], P = .23) and handheld dynamometer strength (difference, 0.4 lb [95% CI, −2.9 to 3.7], P = .82), SF-36 physical health score (difference, 3.4 [95% CI, −0.02 to 7.0], P = .05), SF-36 mental health score (difference, 2.4 [95% CI, −1.2 to 6.0], P = .19), or MMSE score (difference, 0.6 [95% CI, −0.2 to 1.4], P = .17). There were higher scores at 6 months in the SRT group for the SPPB score (difference, 1.1 [95% CI, 0.04 to 2.1, P = .04), SF-36 physical function scale score (difference, 12.2 [95% CI, 3.8 to 20.7], P = .001), and the FPI score (difference, 0.2 [95% CI, 0.04 to 0.4], P = .02). CONCLUSIONS AND RELEVANCE Among patients hospitalized with acute respiratory failure, SRT compared with usual care did not decrease hospital LOS.

Purpose To report additional ocular outcomes of intensive treatment of hyperglycemia, elevated blood pressure, and dyslipidemia in the ACCORD Study. Design Double 2 × 2 factorial multicenter randomized clinical trials in men and women with type 2 diabetes who had established cardiovascular disease and/or cardiovascular risk factors. In the glycemia trial targets of intensive and standard treatment were HbA1c <6.0% and 7.0-7.9%, respectively, and in the blood pressure trial systolic blood pressure of <120 mm Hg and <140 mm Hg, respectively. The dyslipidemia trial compared fenofibrate plus simvastatin vs. placebo plus simvastatin. Participants Of the 5273 ACCORD-Eye participants, 3,472 were enrolled and 2856 had 4-year data (85% of survivors). Methods Eye examinations and fundus photographs were taken at baseline and year 4. Photographs were graded centrally for retinopathy severity and features of macular edema using the Early Treatment Diabetic Retinopathy Study (ETDRS) methods. Primary Outcome Measure 3 or more steps progression on the ETDRS person scale or treatment of retinopathy with photocoagulation or vitrectomy. Results As previously reported, there were significant reductions in the primary outcome in the glycemia and dyslipidemia trials, but no significant effect in the blood pressure trial. Results were similar for retinopathy progression by 1, 2, and 4 or more steps on the person scale and for ≥2 steps on the eye scale. In the subgroup of patients with mild retinopathy at baseline, effect estimates were large (Odds Ratios ∼0.30, P<0.001), but did not reach nominal significance for participants with no retinopathy or for those with moderate to severe retinopathy at baseline. Conclusions Slowing of progression of retinopathy by intensive treatment of glycemia was observed in ACCORD participants, whose average age and diabetes duration were 62 and 10 years, respectively, and who had established cardiovascular disease and/or cardiovascular risk factors. The effect appeared stronger in patients with mild retinopathy. Similar slowing of progression was observed in patients treated with fenofibrate, while no effect was observed with intensive BP treatment. This is the second study to confirm the benefits of fenofibrate in reducing diabetic retinopathy progression and fenofibrate should be considered for treatment of diabetic retinopathy.

Cognitive functioning, mood, and health-related QOL were significantly improved following a 24-week course of the acetylcholinesterase inhibitor donepezil. Toxicities were minimal. We are planning a double blinded, placebo-controlled, phase III trial of donepezil to confirm these favorable results.