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Long-term effects of intensive glucose lowering on cardiovascular outcomes.

ABSTRACT: 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.).

SUBMITTER: ACCORD Study Group

PROVIDER: S-EPMC4083508 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Long-term effects of intensive glucose lowering on cardiovascular outcomes.

Gerstein Hertzel C HC Miller Michael E ME Genuth Saul S Ismail-Beigi Faramarz F Buse John B JB Goff David C DC Probstfield Jeffrey L JL Cushman William C WC Ginsberg Henry N HN Bigger J Thomas JT Grimm Richard H RH Byington Robert P RP Rosenberg Yves D YD Friedewald William T WT

The New England journal of medicine 20110301 9

<h4>Background</h4>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.<h4>Methods</h4>We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a ...[more]

PMID: 21366473

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Project description: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.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.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).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.)

Project description:BackgroundGuidelines recommend intensive blood pressure (BP) lowering in patients at high risk. While placebo-controlled trials have demonstrated 22% reductions in coronary heart disease (CHD) and stroke associated with a 10-mmHg difference in systolic BP, it is unclear if more intensive BP lowering strategies are associated with greater reductions in risk of CHD and stroke. We did a systematic review to assess the effects of intensive BP lowering on vascular, eye, and renal outcomes.Methods and findingsWe systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and July 2011. We included trials that randomly assigned individuals to different target BP levels. We identified 15 trials including a total of 37,348 participants. On average there was a 7.5/4.5-mmHg BP difference. Intensive BP lowering achieved relative risk (RR) reductions of 11% for major cardiovascular events (95% CI 1%-21%), 13% for myocardial infarction (0%-25%), 24% for stroke (8%-37%), and 11% for end stage kidney disease (3%-18%). Intensive BP lowering regimens also produced a 10% reduction in the risk of albuminuria (4%-16%), and a trend towards benefit for retinopathy (19%, 0%-34%, p = 0.051) in patients with diabetes. There was no clear effect on cardiovascular or noncardiovascular death. Intensive BP lowering was well tolerated; with serious adverse events uncommon and not significantly increased, except for hypotension (RR 4.16, 95% CI 2.25 to 7.70), which occurred infrequently (0.4% per 100 person-years).ConclusionsIntensive BP lowering regimens provided greater vascular protection than standard regimens that was proportional to the achieved difference in systolic BP, but did not have any clear impact on the risk of death or serious adverse events. Further trials are required to more clearly define the risks and benefits of BP targets below those currently recommended, given the benefits suggested by the currently available data.

Project description:BackgroundComplication screening is recommended for patients with type 2 diabetes (T2D), but the optimal screening intensity and schedules are unknown. In this study, we evaluated whether intensive versus standard complication screening affects long-term cardiovascular outcomes.MethodsIn this observational study, we included 368 T2D patients referred for intensive screening provided as a 1-day session of clinical-instrumental evaluation of diabetic complications, followed by dedicated counseling. From a total of 4906 patients, we selected control T2D patients who underwent standard complication screening at different visits, by 2:1 propensity score matching. The primary endpoint was the 4p-MACE, defined as cardiovascular mortality, or non-fatal myocardial infarction, stroke, or heart failure. The Cox proportional regression analyses was used to compare outcome occurrence in the two groups, adjusted for residual confounders.Results357 patients from the intensive screening group (out of 368) were matched with 683 patients in the standard screening group. Clinical characteristics were well balanced between the two groups, except for a slightly higher prevalence of microangiopathy in the intensive group (56% vs 50%; standardized mean difference 0.11, p?=?0.1). Median follow-up was 5.6 years. The adjusted incidence of 4p-MACE was significantly lower in the intensive versus standard screening group (HR 0.70; 95% CI 0.52-0.95; p?=?0.02). All components of the primary endpoint had nominally lower rates in the intensive versus standard screening group, which was particularly significant for heart failure (HR 0.43; 95% CI 0.22-0.83; p?=?0.01).ConclusionAmong T2D patients attending a specialist outpatient clinic, intensive complication screening is followed by better long-term cardiovascular outcomes. No significant effect was noted for cardiovascular and all-cause mortality and the benefit was mainly driven by a reduced rate of hospitalization for heart failure.

Project description:BackgroundPrevious studies have demonstrated that intensive blood pressure (BP) lowering treatment reduces the risk of all-cause mortality and provides greater vascular protection for patients with hypertension. Whether intensive BP lowering treatment is associated with such benefits in patients with type 2 diabetes mellitus remain unknown. We aimed to clarify these benefits by method of meta-analysis.MethodsThe PubMed, EMBASE, Science Citation Index and Cochrane Library databases were searched to identify randomized controlled trials (RCT) that fulfilled study inclusion criteria. Two investigators independently extracted and summarized the relevant data of the included trials. Random-effects model was applied to calculate the estimates of all effect measures.ResultsWe included 16 RCTs and our meta-analysis showed that intensive BP lowering treatment vs less intensive BP lowering treatment resulted in significant reductions in the all-cause mortality risk [relative risk (RR), 0.82; 95% CI, 0.70-0.96], major CV events (RR, 0.82; 95% CI, 0.73-0.92, MI (RR, 0.86; 95% CI, 0.77-0.96), stroke (RR, 0.72; 95% CI, 0.60-0.88, CV death (RR, 0.73; 95% CI, 0.58-0.92) and albuminuria progression (RR, 0.91 95% CI, 0.84-0.98). However, intensive BP lowering treatment had no clear effect on non-CV death (RR, 0.97; 95% CI, 0.79-1.20), heart failure (HF) (RR, 0.88; 95% CI, 0.71-1.08) or end-stage kidney disease (ESKD) (RR, 1.00; 95% CI, 0.75-1.33). Subgroup analysis showed that the reduction in all cause-mortality was consistent across most patient groups, and intensive BP lowering treatment had a clear benefit even in patients with systolic blood pressure lower than 140 mm Hg. However, the benefit differed in patients with different CV risk (≥10%: RR, 0.77, 95%CI, 0.64-0.91; <10%: RR, 1.04, 95%CI, 0.84-1.29; Phetero = 0.028).ConclusionsOur data indicate that intensive BP lowering treatment provides greater benefits than less intensive treatment among patients with type 2 diabetes mellitus. Further studies are required to more clearly evaluate the benefits and harms of BP targets below those currently recommended with intensive BP lowering treatment.

Project description:BACKGROUND AND OBJECTIVES:In people with type 2 diabetes, aggressive control of glycemia, BP, and lipids have resulted in conflicting short-term (<5 years) kidney outcomes. We aimed to determine the long-term kidney effects of these interventions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:The Action to Control Cardiovascular Risk in Diabetes (ACCORD) was a multifactorial intervention study in people with type 2 diabetes at high risk for cardiovascular disease (n=10,251), to examine the effects of intensive glycemic control (hemoglobin A1c <6.0% versus 7%-7.9%), BP control (systolic BP <120 mm Hg versus <140 mm Hg) or fenofibrate versus placebo added to simvastatin on cardiovascular events and death. The glycemia trial lasted 3.7 years and participants were followed for another 6.5 years in ACCORDION, the ACCORD Follow-On Study. The post hoc primary composite kidney outcome was defined as incident macroalbuminuria, creatinine doubling, need for dialysis, or death by any cause. Cox proportional hazards regression estimated the effect of each intervention on the composite outcome and individual components. In secondary outcome analyses, competing risk regression was used to account for the risk of death in incident kidney outcomes. Analyses were adjusted for sociodemographics, randomization groups, and clinical factors. RESULTS:There were 988 cases of incident macroalbuminuria, 954 with doubling of creatinine, 351 requiring dialysis, and 1905 deaths. Hazard ratios (HRs) for the composite outcome with intensive glycemic, BP control, and fenofibrate use compared with standard therapy were 0.92 (95% confidence interval [95% CI], 0.86 to 0.98), 1.16 (95% CI, 1.05 to 1.28), and 1.16 (95% CI, 1.06 to 1.27). Multivariable, secondary outcome analyses showed that in the glycemia trial, only macroalbuminuria was significantly decreased (HR, 0.68; 95% CI, 0.59 to 0.77). In the BP and lipid trials, only creatinine doubling was affected (HR, 1.64; 95% CI, 1.30 to 2.06 and HR, 2.00; 95% CI, 1.61 to 2.49, respectively). CONCLUSIONS:In people with type 2 diabetes at high risk for cardiovascular disease, intensive glycemic control may result in a long-term reduction in macroalbuminuria; however, intensive BP control and fenofibrates may increase the risk for adverse kidney events.

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Long-term effects of intensive glucose lowering on cardiovascular outcomes.

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Long-term effects of intensive glucose lowering on cardiovascular outcomes.

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