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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials

R Boussageon, T Bejan-Angoulvant, M Saadatian-Elahi, S Lafont, C Bergeonneau, B Kassai, S Erpeldinger, JM Wright, F Gueyffier, and C Cornu.

Review published: 2011.

CRD summary

This review concluded that the benefits of intensive glucose lowering treatment were limited: a 19% increase in all-cause death and a 43% increase in cardiovascular death could not be ruled out. The benefit to risk ratio in the prevention of vascular events remained uncertain. Given the limitations of the included studies and the analysis undertaken, the authors' cautious conclusions seem appropriate.

Authors' objectives

To determine all-cause and cardiovascular mortality related to intensive glucose-lowering treatment in people with type 2 diabetes.


MEDLINE, EMBASE and Cochrane Database of Systematic Reviews were searched from 1950 to July 2010 without language restrictions; search terms were reported. Reference lists of published meta-analyses were searched.

Study selection

Randomised controlled trials (RCTs) in adults (18 years and over) with type 2 diabetes that assessed the efficacy of intensive glucose-lowering treatment (oral or insulin) versus a standard treatment (standard care), less intensive glycaemic lowering treatment (defined either by a specified HbA1c target or by treatment intensification) or placebo. Primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes included severe hypoglycaemia, macrovascular and microvascular events.

In the RCTs the proportion of males ranged from 29% to 100%. Mean age ranged from 49 to 66 years. Mean baseline HbA1c level ranged from 7.1% to 9.5%. Mean body mass index ranged from 20 to 32. Mean duration of diabetes ranged from less than a year to 12 years. Thirty-nine per cent of patients had a prior cardiovascular event. Intensive and comparator regimens varied considerably across studies. Mean follow-up ranged from one year to 10 years.

Two reviewers independently assessed studies for inclusion.

Assessment of study quality

Two reviewers independently assessed the quality of the RCTs using the Jadad scale.

Data extraction

Two reviewers independently extracted data to calculate relative risks (RR) and 99% confidence intervals (CI) for all-cause and cardiovascular mortality, myocardial infarction, stroke, congestive heart failure, photocoagulation, retinopathy, visual deterioration and blindness, neuropathy, microalbuminuria, renal failure, peripheral vascular events, amputation and severe hypoglycaemia.

Methods of synthesis

Pooled relative risks and 99% CIs were calculated using a fixed-effect meta-analysis when significant heterogeneity was absent; otherwise a random-effects model was used. Heterogeneity was assessed using Cochran Q, I2 and Τ2. Where possible, intention-to-treat analysis was used. The range of absolute risk reductions was calculated from extreme values of risks for the outcome in the control group from three of the RCTs over a five-year period multiplied by the common risk reduction estimate. The number needed to treated or harm was calculated. Sensitivity analyses were conducted to assess the impact of study quality, studies that used withdrawn drugs and studies that included patients with impaired glucose tolerance.

Results of the review

Thirteen randomised controlled trials fulfilled the inclusion criteria (n=34,533 participants). Five trials were double blind controlled trials; three scored 4 on the Jadad scale and two scored 5. Eight trials were open trials; two scored 2 and six scored 3 on the Jadad scale.

Intensive treatment did not significantly affect all-cause mortality (RR 1.04, 99% CI 0.91 to 1.19, I2=42%) and cardiovascular mortality (RR 1.11, 99% CI 0.86 to 1.43, I2=61%).

When restricted to trials with a Jadad score of more than 3, the risk ratio of all-cause mortality was similar (RR 1.06, 99% CI 0.84 to 1.34, I2=32%) and was higher but still not statistically significant for cardiovascular mortality (RR 1.58, 99% CI 0.60 to 4.17, I2=70%). Intensive treatment significantly reduced the rate of non-fatal myocardial infarction (RR 0.85, 99% CI 0.74 to 0.96, I2=0%) and microalbuminuria (RR 0.90, 99% CI 0.85 to 0.96, I2=31%) and significantly increased the incidence of severe hypoglycaemia (RR 2.33, 99% CI 1.62 to 3.36, I2=63%).

The number needed to treat was 117 to 150 to avoid one myocardial infarction and 32 to 142 to avoid one episode of microalbuminuria; one severe episode of hypoglycaemia would occur for every 15 to 52 patients (see Other Publications of Related Interest).

Authors' conclusions

There were limited benefits of intensive glucose-lowering treatment on all-cause and cardiovascular mortality. A 19% increase in all-cause mortality and a 43% increase in cardiovascular mortality could not be ruled out. The benefit to risk ratio of intensive glucose lowering treatment in the prevention of macrovascular and microvascular events remained uncertain.

CRD commentary

The review addressed a clear research question supported by appropriate inclusion criteria. Relevant sources were searched without language restrictions. There was no specific search for unpublished studies and although the Cochrane Database of Systematic Reviews was searched, the controlled trial database was not. Therefore, studies may have been missed.

Each stage of the review process was conducted in duplicate, which reduced risks of error and bias. Trial quality was assessed using recognised criteria and the results were taken into consideration in the analysis. Clinically heterogeneous studies were pooled, which made the reliability and generalisability of the pooled results uncertain; the authors investigated some aspects of between-study heterogeneity.

The authors' cautious conclusions seem appropriate given the limitations of the included studies and analysis of heterogeneous studies.

Implications of the review for practice and research

Practice: The authors did not state implications for practice.

Research: The authors stated that double blind RCTs were needed to establish the best therapeutic approach in people with type 2 diabetes.


Not stated.

Bibliographic details

Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, Lafont S, Bergeonneau C, Kassai B, Erpeldinger S, Wright JM, Gueyffier F, Cornu C. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 2011; 343:d4169. [PMC free article: PMC3144314] [PubMed: 21791495]

Other publications of related interest

Correction: Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 2011; 343:d5301.

Indexing Status

Subject indexing assigned by NLM


Adult; Aged; Albuminuria /etiology /mortality; Blood Glucose /metabolism; Cause of Death; Diabetes Mellitus, Type 2 /drug therapy /mortality; Diabetic Angiopathies /drug therapy /mortality; Female; Humans; Hypoglycemia /chemically induced; Hypoglycemic Agents /therapeutic use; Male; Microcirculation; Middle Aged; Myocardial Infarction /mortality; Randomized Controlled Trials as Topic; Risk Reduction Behavior; Treatment Outcome; Young Adult



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 21791495

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