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Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial.

ABSTRACT: BACKGROUND:Hyperglycaemia could substantially increase the risk of ischaemic heart disease in patients with type 2 diabetes. We investigated whether intensive lowering of glucose concentrations affects risk. METHODS:We assessed 10,251 adults aged 40-79 years with established type 2 diabetes, mean glycated haemoglobin A1c (HbA1c) concentration of 67 mmol/mol (8·3%), and risk factors for ischaemic heart disease enrolled in the ACCORD trial. Participants were assigned to intensive or standard therapy (target HbA1c less than 42 or 53-63 mmol/mol [less than 6·0% or 7·0-7·9%], respectively). We assessed fatal or non-fatal myocardial infarction, coronary revascularisation, unstable angina, and new angina during active treatment (mean 3·7 years) plus a further mean 1·2 years. This trial is registered with ClinicalTrials.gov, number NCT00000620. FINDINGS:Myocardial infarction was less frequent in the intensive than in the standard therapy group during active treatment (hazard ratio [HR] 0·80, 95% CI 0·67-0·96; p=0·015) and overall (0·84, 0·72-0·97; p=0·02). Findings were similar for combined myocardial infarction, coronary revascularisation, and unstable angina (active treatment HR 0·89, 95% CI 0·79-0·99, overall 0·87 0·79-0·96) and for coronary revascularisation alone (0·84, 0·75-0·94) and unstable angina alone (0·81, 0·67-0·97) during full follow-up. With lowest achieved HbA1C concentrations included as a time-dependent covariate, all hazards became non-significant. INTERPRETATION:Raised glucose concentration is a modifiable risk factor for ischaemic heart disease in middle-aged people with type 2 diabetes and other cardiovascular risk factors. FUNDING:National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Eye Intitute, and Centers for Disease Control and Prevention.

SUBMITTER: Gerstein HC

PROVIDER: S-EPMC4397008 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial.

Gerstein Hertzel C HC Miller Michael E ME Ismail-Beigi Faramarz F Largay Joe J McDonald Charlotte C Lochnan Heather A HA Booth Gillian L GL

Lancet (London, England) 20140731 9958

<h4>Background</h4>Hyperglycaemia could substantially increase the risk of ischaemic heart disease in patients with type 2 diabetes. We investigated whether intensive lowering of glucose concentrations affects risk.<h4>Methods</h4>We assessed 10,251 adults aged 40-79 years with established type 2 diabetes, mean glycated haemoglobin A1c (HbA1c) concentration of 67 mmol/mol (8·3%), and risk factors for ischaemic heart disease enrolled in the ACCORD trial. Participants were assigned to intensive or ...[more]

PMID: 25088437

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Project description:BackgroundDiabetes is now a global epidemic, but most cases are now in low- and middle-income countries. Diabetes self-management education (DSME) is key to enabling patients to manage their chronic condition and can reduce the occurrence of costly and devastating complications. However, there is limited evidence on the effectiveness of different DSME programmes in resource limited settings.MethodsWe conducted an unblinded, parallel-group, individually-randomised controlled trial at the University of Calabar Teaching Hospital (Nigeria) to evaluate whether an intensive and systematic DSME programme, using structured guidelines, improved glycaemic control compared to the existing ad hoc patient education (clinical practice was unchanged). Eligible patients (?18 years, HbA1c > 8.5% and physically able to participate) were randomly allocated by permuted block randomisation to participate for six months in either an intensive or conventional education group. The primary outcome was HbA1c (%) at six-months.ResultsWe randomised 59 participants to each group and obtained six-month HbA1c outcomes from 53 and 51 participants in the intensive and conventional education groups, respectively. Intensive group participants had a mean six-month HbA1c (%) of 8.4 (95% CI: 8 to 8.9), while participants in the conventional education group had a mean six-month HbA1c (%) of 10.2 (95% CI: 9.8 to 10.7). The difference was statistically (P < 0.0001) and clinically significant, with intensive group participants having HbA1c outcomes on average -1.8 (95% CI: -2.4 to -1.2) percentage points lower than conventional group participants. Results were robust to adjustment for a range of covariates and multiple imputation of missing outcome data.ConclusionsThis study demonstrates the effectiveness of a structured, guideline-based DSME intervention in a LMIC setting versus a pragmatic comparator. The intervention is potentially replicable at other levels of the Nigerian healthcare system and in other LMICs, where nurses/diabetes educators can run the programme.Trial registrationPan African Clinical Trial Registry PACTR20130200047835.

Project description:IntroductionCritically ill patients can develop hyperglycaemia even if they do not have diabetes. Intensive insulin therapy decreases morbidity and mortality rates in patients in a surgical intensive care unit (ICU) and decreases morbidity in patients in a medical ICU. The effect of this therapy on patients in a mixed medical/surgical ICU is unknown. Our goal was to assess whether the effect of intensive insulin therapy, compared with standard therapy, decreases morbidity and mortality in patients hospitalised in a mixed ICU.MethodsThis is a prospective, randomised, non-blinded, single-centre clinical trial in a medical/surgical ICU. Patients were randomly assigned to receive either intensive insulin therapy to maintain glucose levels between 80 and 110 mg/dl (4.4 to 6.1 mmol/l) or standard insulin therapy to maintain glucose levels between 180 and 200 mg/dl (10 and 11.1 mmol/l). The primary end point was mortality at 28 days.ResultsOver a period of 30 months, 504 patients were enrolled. The 28-day mortality rate was 32.4% (81 of 250) in the standard insulin therapy group and 36.6% (93 of 254) in the intensive insulin therapy group (Relative Risk [RR]: 1.1; 95% confidence interval [CI]: 0.85 to 1.42). The ICU mortality in the standard insulin therapy group was 31.2% (78 of 250) and 33.1% (84 of 254) in the intensive insulin therapy group (RR: 1.06; 95%CI: 0.82 to 1.36). There was no statistically significant reduction in the rate of ICU-acquired infections: 33.2% in the standard insulin therapy group compared with 27.17% in the intensive insulin therapy group (RR: 0.82; 95%CI: 0.63 to 1.07). The rate of hypoglycaemia (< or = 40 mg/dl) was 1.7% in the standard insulin therapy group and 8.5% in the intensive insulin therapy group (RR: 5.04; 95% CI: 1.20 to 21.12).ConclusionsIIT used to maintain glucose levels within normal limits did not reduce morbidity or mortality of patients admitted to a mixed medical/surgical ICU. Furthermore, this therapy increased the risk of hypoglycaemia.Trial registrationclinicaltrials.gov Identifiers: 4374-04-13031; 094-2 in 000966421.

Project description:Aims/hypothesisIn patients with diabetes, intensive glycaemic control reduces microvascular complications. However, severe hypoglycaemia frequently complicates intensive glycaemic control. Blood biomarkers that predict successful intensification of glycaemic control in patients with type 2 diabetes without the development of severe hypoglycaemia would advance patient care. In patients who received intensive treatment for type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesised that insulin deficiency and islet autoantibodies would be associated with severe hypoglycaemia and failure to achieve near-normal glycaemia (HbA1c <6.0% [42 mmol/mol]).MethodsA nested case-control design was used. Cases (n = 326) were defined as participants having severe hypoglycaemia and failure to achieve an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death. Controls (n = 1,075) were those who achieved an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death without severe hypoglycaemia. Each case was matched (for race, age and BMI) by up to four controls. Baseline insulin deficiency (fasting C-peptide ≤0.15 nmol/l) and islet autoantibodies (glutamic acid decarboxylase [GAD], tyrosine phosphatase-related islet antigen 2 [IA2], insulin [IAA] and zinc transporter 8 [ZnT8]) were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used on the full cohort and after removal of patients who died and their respective controls.ResultsSevere hypoglycaemia accompanied by an inability to achieve an HbA1c level of <6.0% (42 mmol/mol) was associated with insulin deficiency (adjusted OR 23.2 [95% CI 9.0, 59.5], p < 0.0001), the presence of IAA autoantibodies or baseline insulin use (adjusted OR 3.8 [95% CI 2.7, 5.3], p < 0.0001), GAD autoantibodies (OR 3.9 [95% CI 2.5, 6.0], p < 0.0001), IA2 autoantibodies (OR 16.7 [95% CI 3.9, 71.6], p = 0.0001) and ZnT8 autoantibodies (adjusted OR 3.9 [95% CI 1.2, 12.4], p = 0.02).ConclusionsC-peptide and islet autoantibodies may serve as biomarkers to predict the risk of severe hypoglycaemia during intensification of type 2 diabetes treatment.Trial registrationClinicalTrials.gov NCT00000620 (original ACCORD study).

Project description:ObjectiveTo assess the effect of targeting intensive glycaemic control versus conventional glycaemic control on all cause mortality and cardiovascular mortality, non-fatal myocardial infarction, microvascular complications, and severe hypoglycaemia in patients with type 2 diabetes.DesignSystematic review with meta-analyses and trial sequential analyses of randomised trials.Data sourcesCochrane Library, Medline, Embase, Science Citation Index Expanded, LILACS, and CINAHL to December 2010; hand search of reference lists and conference proceedings; contacts with authors, relevant pharmaceutical companies, and the US Food and Drug Administration.Study selectionRandomised clinical trials comparing targeted intensive glycaemic control with conventional glycaemic control in patients with type 2 diabetes. Published and unpublished trials in all languages were included, irrespective of predefined outcomes.Data extractionTwo reviewers independently assessed studies for inclusion and extracted data related to study methods, interventions, outcomes, risk of bias, and adverse events. Risk ratios with 95% confidence intervals were estimated with fixed and random effects models.ResultsFourteen clinical trials that randomised 28,614 participants with type 2 diabetes (15,269 to intensive control and 13,345 to conventional control) were included. Intensive glycaemic control did not significantly affect the relative risks of all cause (1.02, 95% confidence interval 0.91 to 1.13; 28,359 participants, 12 trials) or cardiovascular mortality (1.11, 0.92 to 1.35; 28,359 participants, 12 trials). Trial sequential analyses rejected a relative risk reduction above 10% for all cause mortality and showed insufficient data on cardiovascular mortality. The risk of non-fatal myocardial infarction may be reduced (relative risk 0.85, 0.76 to 0.95; P=0.004; 28,111 participants, 8 trials), but this finding was not confirmed in trial sequential analysis. Intensive glycaemic control showed a reduction of the relative risks for the composite microvascular outcome (0.88, 0.79 to 0.97; P=0.01; 25,600 participants, 3 trials) and retinopathy (0.80, 0.67 to 0.94; P=0.009; 10,793 participants, 7 trials), but trial sequential analyses showed that sufficient evidence had not yet been reached. The estimate of an effect on the risk of nephropathy (relative risk 0.83, 0.64 to 1.06; 27,769 participants, 8 trials) was not statistically significant. The risk of severe hypoglycaemia was significantly increased when intensive glycaemic control was targeted (relative risk 2.39, 1.71 to 3.34; 27,844 participants, 9 trials); trial sequential analysis supported a 30% increased relative risk of severe hypoglycaemia.ConclusionIntensive glycaemic control does not seem to reduce all cause mortality in patients with type 2 diabetes. Data available from randomised clinical trials remain insufficient to prove or refute a relative risk reduction for cardiovascular mortality, non-fatal myocardial infarction, composite microvascular complications, or retinopathy at a magnitude of 10%. Intensive glycaemic control increases the relative risk of severe hypoglycaemia by 30%.

Dataset Information

Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial.

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Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial.

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