William T. Friedewald

Effects of intensive glucose lowering in type 2 diabetes

BACKGROUND Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. METHODS In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. RESULTS At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001). CONCLUSIONS As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

Effects of intensive blood-pressure control in type 2 diabetes mellitus.

BACKGROUND There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events. METHODS A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001). CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.)

Long-Term Effects of Intensive Glucose Lowering on Cardiovascular Outcomes

BACKGROUND Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events. METHODS We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial. RESULTS Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P=0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups. CONCLUSIONS As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.).

Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline Brain Injury Treatment Trial (COBRIT).

CONTEXT Traumatic brain injury (TBI) is a serious public health problem in the United States, yet no treatment is currently available to improve outcome after TBI. Approved for use in TBI in 59 countries, citicoline is an endogenous substance offering potential neuroprotective properties as well as facilitated neurorepair post injury. OBJECTIVE To determine the ability of citicoline to positively affect functional and cognitive status in persons with complicated mild, moderate, and severe TBI. DESIGN, SETTING, AND PATIENTS The Citicoline Brain Injury Treatment Trial (COBRIT), a phase 3, double-blind randomized clinical trial conducted between July 20, 2007, and February 4, 2011, among 1213 patients at 8 US level 1 trauma centers to investigate effects of citicoline vs placebo in patients with TBI classified as complicated mild, moderate, or severe. INTERVENTION Ninety-day regimen of daily enteral or oral citicoline (2000 mg) or placebo. MAIN OUTCOME MEASURES Functional and cognitive status, assessed at 90 days using the TBI-Clinical Trials Network Core Battery. A global statistical test was used to analyze the 9 scales of the core battery. Secondary outcomes were functional and cognitive improvement, assessed at 30, 90, and 180 days, and examination of the long-term maintenance of treatment effects. RESULTS Rates of favorable improvement for the Glasgow Outcome Scale-Extended were 35.4% in the citicoline group and 35.6% in the placebo group. For all other scales the rate of improvement ranged from 37.3% to 86.5% in the citicoline group and from 42.7% to 84.0% in the placebo group. The citicoline and placebo groups did not differ significantly at the 90-day evaluation (global odds ratio [OR], 0.98 [95% CI, 0.83-1.15]); in addition, there was no significant treatment effect in the 2 severity subgroups (global OR, 1.14 [95% CI, 0.88-1.49] and 0.89 [95% CI, 0.72-1.49] for moderate/severe and complicated mild TBI, respectively). At the 180-day evaluation, the citicoline and placebo groups did not differ significantly with respect to the primary outcome (global OR, 0.87 [95% CI, 0.72-1.04]). CONCLUSION Among patients with traumatic brain injury, the use of citicoline compared with placebo for 90 days did not result in improvement in functional and cognitive status. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00545662.

Nine-year effects of 3.7 years of intensive glycemic control on cardiovascular outcomes

OBJECTIVE In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, ∼4 years of intensive versus standard glycemic control in participants with type 2 diabetes and other cardiovascular risk factors had a neutral effect on the composite cardiovascular outcome, increased cardiovascular and total mortality, and reduced nonfatal myocardial infarction. Effects of the intervention during prolonged follow-up were analyzed. RESEARCH DESIGN AND METHODS All surviving ACCORD participants were invited to participate in the ACCORD Follow-on (ACCORDION) study, during which participants were treated according to their health care provider’s judgment. Cardiovascular and other health-related outcomes were prospectively collected and analyzed using an intention-to-treat approach according to the group to which participants were originally allocated. RESULTS A total of 8,601 people, representing 98% of those who did not suffer a primary outcome or death during the ACCORD trial, were monitored for a median of 8.8 years and a mean of 7.7 years from randomization. Intensive glucose lowering for a mean of 3.7 years had a neutral long-term effect on the primary composite outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), death from any cause, and an expanded composite outcome that included all-cause death. Moreover, the risk of cardiovascular mortality noted during the active phase (hazard ratio 1.49; 95% CI 1.19, 1.87; P < 0.0001) decreased (HR 1.20; 95% CI 1.03, 1.39; P = 0.02). CONCLUSIONS In high-risk people with type 2 diabetes monitored for 9 years, a mean of 3.7 years of intensive glycemic control had a neutral effect on death and nonfatal cardiovascular events but increased cardiovascular-related death.

Periodontal Infection, Systemic Inflammation, and Insulin Resistance Results from the Continuous National Health and Nutrition Examination Survey (NHANES) 1999–2004

OBJECTIVE Adverse microbial exposures might contribute to diabetogenesis. We hypothesized that clinical periodontal disease (a manifestation of microbial exposures in dysbiotic biofilms) would be related to insulin resistance among diabetes-free participants. The roles of inflammatory mediation and effect modification were also studied. RESEARCH DESIGN AND METHODS The continuous National Health and Nutrition Examination Survey 1999–2004 enrolled 3,616 participants (51% women) who received a periodontal examination and fasting blood draw. Participants were mean age (± SD) 43 ± 17 years and 28% Hispanic, 52% Caucasian, 17% African American, and 3% other. Log-transformed values of the homeostasis model assessment of insulin resistance (HOMA-IR) or HOMA-IR ≥3.30 (75th percentile) were regressed across full-mouth periodontal probing depth (PD) levels using linear and logistic models. White blood cell (WBC) count and C-reactive protein (CRP) were considered as either mediators or effect modifiers in separate analyses. Risk ratios (RRs) stem from marginal predictions derived from the logistic model. Results were adjusted for multiple periodontal disease and insulin resistance risk factors. RESULTS In linear regression, geometric mean HOMA-IR levels increased by 1.04 for every 1-mm PD increase (P = 0.007). WBC mediated 6% of the association (P < 0.05). Among participants with WBC ≤6.4 × 109, PD was unrelated to HOMA-IR ≥3.30. Fourth-quartile PD was associated with HOMA-IR ≥3.30 among participants with WBC >7.9 × 109; RR 2.60 (1.36–4.97) (P for interaction = 0.05). Findings were similar among participants with CRP >3.0 mg/L (P for interaction = 0.04). CONCLUSIONS Periodontal infection was associated with insulin resistance in a nationally representative U.S. sample of diabetes-free adults. These data support the role of inflammation as both mediator and effect modifier of the association.

The citicoline brain injury treatment (COBRIT) trial: design and methods.

Traumatic brain injury (TBI) is a major cause of death and disability. In the United States alone approximately 1.4 million sustain a TBI each year, of which 50,000 people die, and over 200,000 are hospitalized. Despite numerous prior clinical trials no standard pharmacotherapy for the treatment of TBI has been established. Citicoline, a naturally occurring endogenous compound, offers the potential of neuroprotection, neurorecovery, and neurofacilitation to enhance recovery after TBI. Citicoline has a favorable side-effect profile in humans and several meta-analyses suggest a benefit of citicoline treatment in stroke and dementia. COBRIT is a randomized, double-blind, placebo-controlled, multi-center trial of the effects of 90 days of citicoline on functional outcome in patients with complicated mild, moderate, and severe TBI. In all, 1292 patients will be recruited over an estimated 32 months from eight clinical sites with random assignment to citicoline (1000 mg twice a day) or placebo (twice a day), administered enterally or orally. Functional outcomes are assessed at 30, 90, and 180 days after the day of randomization. The primary outcome consists of a set of measures that will be analyzed as a composite measure using a global test procedure at 90 days. The measures comprise the following core battery: the California Verbal Learning Test II; the Controlled Oral Word Association Test; Digit Span; Extended Glasgow Outcome Scale; the Processing Speed Index; Stroop Test part 1 and Stroop Test part 2; and Trail Making Test parts A and B. Secondary outcomes include survival, toxicity, and rate of recovery.