Glucose targets for preventing diabetic kidney disease and its progression
Abstract
Background
Diabetes is the leading cause of end‐stage kidney disease (ESKD) around the world. Blood pressure lowering and glucose control are used to reduce diabetes‐associated disability including kidney failure. However there is a lack of an overall evidence summary of the optimal target range for blood glucose control to prevent kidney failure.
Objectives
To evaluate the benefits and harms of intensive (HbA1c < 7% or fasting glucose levels < 120 mg/dL versus standard glycaemic control (HbA1c ≥ 7% or fasting glucose levels ≥ 120 mg/dL for preventing the onset and progression of kidney disease among adults with diabetes.
Search methods
We searched the Cochrane Kidney and Transplant Specialised Register up to 31 March 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Selection criteria
Randomised controlled trials evaluating glucose‐lowering interventions in which people (aged 14 year or older) with type 1 or 2 diabetes with and without kidney disease were randomly allocated to tight glucose control or less stringent blood glucose targets.
Data collection and analysis
Two authors independently assessed studies for eligibility and risks of bias, extracted data and checked the processes for accuracy. Outcomes were mortality, cardiovascular complications, doubling of serum creatinine (SCr), ESKD and proteinuria. Confidence in the evidence was assessing using GRADE. Summary estimates of effect were obtained using a random‐effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes.
Main results
Fourteen studies involving 29,319 people with diabetes were included and 11 studies involving 29,141 people were included in our meta‐analyses. Treatment duration was 56.7 months on average (range 6 months to 10 years). Studies included people with a range of kidney function. Incomplete reporting of key methodological details resulted in uncertain risks of bias in many studies. Using GRADE assessment, we had moderate confidence in the effects of glucose lowering strategies on ESKD, all‐cause mortality, myocardial infarction, and progressive protein leakage by kidney disease and low or very low confidence in effects of treatment on death related to cardiovascular complications and doubling of serum creatinine (SCr).
For the primary outcomes, tight glycaemic control may make little or no difference to doubling of SCr compared with standard control (4 studies, 26,874 participants: RR 0.84, 95% CI 0.64 to 1.11; I2= 73%, low certainty evidence), development of ESKD (4 studies, 23,332 participants: RR 0.62, 95% CI 0.34 to 1.12; I2= 52%; low certainty evidence), all‐cause mortality (9 studies, 29,094 participants: RR 0.99, 95% CI 0.86 to 1.13; I2= 50%; moderate certainty evidence), cardiovascular mortality (6 studies, 23,673 participants: RR 1.19, 95% CI 0.73 to 1.92; I2= 85%; low certainty evidence), or sudden death (4 studies, 5913 participants: RR 0.82, 95% CI 0.26 to 2.57; I2= 85%; very low certainty evidence). People who received treatment to achieve tighter glycaemic control probably experienced lower risks of non‐fatal myocardial infarction (5 studies, 25,596 participants: RR 0.82, 95% CI 0.67 to 0.99; I2= 46%, moderate certainty evidence), onset of microalbuminuria (4 studies, 19,846 participants: RR 0.82, 95% CI 0.71 to 0.93; I2= 61%, moderate certainty evidence), and progression of microalbuminuria (5 studies, 13,266 participants: RR 0.59, 95% CI 0.38 to 0.93; I2= 75%, moderate certainty evidence). In absolute terms, tight versus standard glucose control treatment in 1,000 adults would lead to between zero and two people avoiding non‐fatal myocardial infarction, while seven adults would avoid experiencing new‐onset albuminuria and two would avoid worsening albuminuria.
Authors' conclusions
This review suggests that people who receive intensive glycaemic control for treatment of diabetes had comparable risks of kidney failure, death and major cardiovascular events as people who received less stringent blood glucose control, while experiencing small clinical benefits on the onset and progression of microalbuminuria and myocardial infarction. The adverse effects of glycaemic management are uncertain. Based on absolute treatment effects, the clinical impact of targeting an HbA1c < 7% or blood glucose < 6.6 mmol/L is unclear and the potential harms of this treatment approach are largely unmeasured.
PICOs
Plain language summary
Glucose targets for preventing diabetic kidney disease and its progression
What is the issue?
In many parts of the world, diabetes is the most common reason that people experience kidney failure and need treatment with a kidney transplant or dialysis. Disability (blindness, limb loss, kidney failure) due to diabetes is caused by high blood glucose (sugar) levels. An important question is whether extra treatment to control blood glucose levels to near normal can safely prevent the health consequences of diabetes including lower life expectancy and loss of kidney function, without causing problems such as low blood glucose leading to loss of awareness or seizures. Some medical care of diabetes includes careful blood glucose control to low levels (measured by a blood test called the HbA1C) through the use of extra medication and careful blood glucose monitoring with the help of health professionals.
What did we do?
We looked at the evidence for tighter blood glucose control (lower blood glucose in the long term, that is HbA1c < 7% ) compared with less tight blood glucose control (HbA1c > 7%) in people who have either type 1 or type 2 diabetes. Blood glucose was achieved by any sort of treatment including pills or insulin.
What did we find?
Fourteen studies involving 29,319 people with at risk of diabetes complications were included and 11 studies involving 29,141 people were included in our analyses. Tighter blood glucose control generally didn't show any benefits for patients compared to less tight glucose control. There was no difference in the risks for patients on kidney failure, death, or heart disease complications. A very small number of patients (1 in every 1000 treated each year) might avoid a heart attack with more intense blood glucose management. Some patients would expect to have less protein leakage through kidney function although the clinical impact of this benefit is unclear in the long term. The potential problems with treatment, such as side effects and risks of very low blood glucose (hypoglycaemia) were not generally measured in the studies.
Our conclusions
The review concludes that people with diabetes receive uncertain benefits from tighter blood glucose control in the long‐term and the immediate complications of this treatment approach are difficult to know accurately.
Authors' conclusions
Summary of findings
| Tight glycaemic control compared with non‐tight control for preventing DKD and its progression | ||||||
| Patient or population: patients with diabetes Intervention: tight glycaemic control Comparison: non‐tight glycaemic control | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Confidence of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Non‐tight control | Tight control | |||||
| Doubling serum creatinine 8.3 years | 39 per 1000 | 33 per 1000 (24.95 to 43.29) NNT: 167 | RR 0.84 (0.64 to 1.11) | 26,874 (4) | ⊕⊕⊝⊝ | Imprecision (‐1) Heterogeneity (‐1) |
| ESKD 5.9 years | 3 per 1000 | 2 per 1000 (1.02 to 3.36) NNT: 1000 | RR 0.62 (0.34 to 1.12) | 23,332 (4) | ⊕⊕⊝⊝ | Imprecision (‐1) Heterogeneity (‐1) |
| Sudden death 4.6 years | 2 per 1000 | 2 per 1000 (0.52 to 5.14) NNT: 0 | RR 0.82 (0.26 to 2.57) | 5,913 (4) | ⊕⊝⊝⊝ | Study limitation (‐1) Imprecision (‐1) Heterogeneity (‐1) |
| All‐cause mortality 5.6 years | 16 per 1000 | 16 per 1000 (13.76‐18.08) NNT: 0 | RR 0.99 (0.86 to 1.13) | 29,094 (9) | ⊕⊕⊕⊝ | Imprecision (‐1) |
| Cardiovascular mortality 4.4 years | 9 per 1000 | 11 per 1000 (6.57 to 17.28) NNH: 500 | RR 1.19 (0.73 to 1.92) | 23,673 (6) | ⊕⊕⊝⊝ | Imprecision (‐1) Heterogeneity (‐1) |
| Non‐fatal myocardial infarction 5.6 years | 8 per 1000 | 7 per 1000 (5.36 to 7.92) NNT: 1000 | RR 0.82 (0.67 to 0.99) | 25,596 (5) | ⊕⊕⊕⊝ | Study limitation (‐1) |
| Onset microalbuminuria 5.4 years | 46 per 1000 | 39 per 1000 (35.42 to 43.24) NNT: 143 | RR 0.85 (0.77 to 0.94) | 19,933 (4) | ⊕⊕⊕⊝ | Heterogeneity (‐1) |
| Progression of microalbuminuria 5.8 years | 4 per 1000 | 2 per 1000 (1.52 to 3.72) NNT: 500 | RR 0.59 (0.38 to 0.93) | 13,266 (5) | ⊕⊕⊕⊝ | Heterogeneity (‐1) |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is calculated from data in the meta‐analyses. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). We did not downgrade for reason of publication bias as insufficient studies contributed to treatment estimates to draw meaningful conclusions | ||||||
| GRADE Working Group grades of evidence | ||||||
| ESKD ‐ end‐stage kidney disease | ||||||
Background
Description of the condition
The prevalence of diabetes is increasing worldwide (IDF 2015) and people with type 1 or type 2 diabetes are at high risk for a number of serious health problems, including cardiovascular complications, premature death, end‐stage kidney disease (ESKD), blindness, and limb loss (CDC 2011). Diabetes is estimated to cause 43 million people around the world to live with disability each year (Murray 2012).
Diabetic kidney disease (DKD), which refers to kidney disease caused by diabetes (also called diabetic nephropathy), is the leading cause of people experiencing ESKD. In the USA alone, diabetes is responsible for 44% of people needing treatment with dialysis or transplantation (USRDS 2011). Diabetes mellitus affects 3% to 4% of adults worldwide, with prevalence projected to double over the first three decades of the 21st century (Wild 2004). Chronic kidney disease (CKD) generally occurs in 25& to 40% of patients with diabetes within 20 to 25 years of onset (Ritz 1999) but although its incidence has decreased, diabetes is still the most important cause of ESKD in industrialised countries (USRDS 2013). Recent data have shown a reduction of the incidence of DKD in patients whose diagnosis occurred in more recent years, indicating a most favourable prognosis of type 1 diabetes when diagnosed in the early years, and a lower incidence of ESKD (Finne 2005), Similar studies also suggest that early‐onset type 2 diabetes mellitus is associated with substantially increased incidence of ESKD and mortality in middle age (Pavkov 2006).
Description of the intervention
The risk of kidney disease among people with diabetes is associated with blood glucose control (DCCT 1986; Krolewski 1995; UKPDS 1998). Consequently, the role of tight glycaemic control (glycated haemoglobin (HbA1c) < 7% or fasting glucose levels < 120 mg/dL (6.7 mmol/L)) on the onset and progression of DKD has been explored by several randomised controlled trials (RCTs) in patients with type 1 (DCCT 1986) and type 2 (Ismail 2010; Moritz 2009; Patel 2008; UKPDS 1998) diabetes. These studies have specifically compared the effect of more intensive treatment to target lower fasting plasma glucose levels or HbA1c on kidney outcomes compared with conventional hypoglycaemic therapy.
While there is an association between higher blood glucose levels and poorer clinical outcomes among people with diabetes, the impact of glucose‐lowering treatment to tighter glucose treatment targets remains uncertain and potential harms including hypoglycaemia are increased. A meta‐analysis of tight blood glucose control showed that people receiving intensive antihyperglycaemic treatment had similar risks of all‐cause mortality and cardiovascular mortality as people with conventional blood glucose targets and insufficient information was available in accrued clinical studies to evaluate benefits of tighter glycaemia targets on non‐fatal myocardial infarction, composite microvascular complications, or retinopathy (Hemmingsen 2011), while people allocated to lower blood glucose levels experienced a 30% increased risk of severe hypoglycaemia.
How the intervention might work
Hyperglycaemia is a crucial factor in the development of DKD due to tissue glycosylation including glomerular and mesangial cells. Three mechanisms have been postulated that explain pathways of glucose‐mediated tissue damage: non‐enzymatic glycosylation that generates advanced glycosylation end products; activation of protein kinase C (PKC); and acceleration of the aldose reductase pathway. RCTs have shown that people receiving tight glycaemic control experience less new microalbuminuria, while the impact of tighter glucose targets on the progression from microalbuminuria to overt kidney failure (doubling serum creatinine (SCr) and ESKD), remains unclear. Conflicting results on the role played by tight glycaemic control on cardiovascular events and total mortality among people with kidney disease have been reported (Duckworth 2009; Patel 2008), with a recent study showing an increased risk of death associated with intensive glucose treatment (Gerstain 2008). Hypoglycaemia is the major risk of intensive glucose treatment and a higher rate of severe hypoglycaemia has been consistently reported with tight glucose control (DCCT 1986; UKPDS 1998). Although mild episodes generally may be well tolerated, severe hypoglycaemia can cause serious injury, unconsciousness, seizures, coma, myocardial ischaemia, angina, residual neurological impairment, or death (Desouza 2003).
Why it is important to do this review
The benefits and harms of tight versus standard blood glucose control for cardiovascular and kidney‐related outcomes in people with diabetes and kidney disease have not been formally summarised in a systematic review. This review attempts to provide this overview of the existing evidence.
Objectives
To evaluate the benefits and harms of intensive (HbA1c < 7% or fasting glucose levels < 120 mg/dL versus standard glycaemic control (HbA1c ≥ 7% or fasting glucose levels ≥120 mg/dL for preventing the onset and progression of kidney disease among adults with diabetes.
Methods
Criteria for considering studies for this review
Types of studies
All RCTs and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) that evaluated the effect of tight versus standard glycaemic control administered to patients with type 1 or type 2 diabetes with or without kidney disease were included. Studies were included if they reported follow‐up data during treatment of 6 months or longer.
Types of participants
Inclusion criteria
People with type 1 or type 2 diabetes, irrespective of blood pressure (BP) and baseline blood glucose levels
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Without kidney disease: defined as a normal estimated (e) or measured (m) glomerular filtration rate (GFR) (> 90 mL/min) and an albumin excretion rate of < 30 mg/d on a timed specimen or urinary albumin/creatinine ratio (ACR) < 30 mg/g confirmed with three serial measurements)
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With kidney disease
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Normal or impaired GFR (> 90 mL/min) with or without microalbuminuria defined as an albumin excretion rate between 30 and 300 mg/d or 20 to 200 μg/min on a timed specimen or urinary ACR between 30 and 300 mg/g, confirmed with three serial measurements
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Macroalbuminuria defined as an albumin excretion rate ≥ 300 mg/d or ≥ 200 μg/min on a timed specimen or urinary ACR ≥ 300 mg/g, confirmed with three serial measurements.
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Exclusion criteria
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People with diabetes and CKD not caused by diabetes, as proven by kidney biopsy
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Children and adolescents aged < 14 years
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Pregnant women.
Types of interventions
The interventions of interest were tight glycaemic control versus standard glycaemic control.
Tight glycaemic control was defined by allocation to a treatment approach targeting an HbA1c < 7% or fasting glucose levels < 120 mg/dL (6.7 mmol/L).
Standard (conventional) glycaemic control was defined by allocation to a treatment approach targeting HbA1c ≥ 7% or fasting glycaemic control ≥ 120 mg/dL (6.7 mmol/L) or as defined by the authors, including standard practice clinical care. Three sub‐categories of conventional control (HbA1C: i. 7.0% to 8.5%; ii. 8.5% to 10.0%; iii. > 10.0%) were considered.
Glycaemic control could be achieved by any blood glucose‐lowering approach, administered at any dose and for a duration of at least six months. We considered studies in which people were randomly allocated to placebo or standard care (no targeted treatment) and studies that allocated participants to two different treatments or different doses of the same treatment as long as the glucose target was tight versus conventional in the study.
Types of outcome measures
Primary outcomes
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Doubling of SCr
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ESKD (GFR < 15 mL/min for 3 months or longer, treated with dialysis, transplantation or symptomatic management)
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Death (any cause, cardiovascular, sudden) or nonfatal myocardial infarction or stroke
Secondary outcomes
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Onset, progression, or regression of microalbuminuria
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Urinary ACR at the end of treatment or change between beginning and end of treatment
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SCr (mg/dL, μmol/L) at the end of treatment or change in SCr between beginning and end of treatment
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Creatinine clearance (CrCl) or GFR (any measure) at the end of treatment or change (any measure) between beginning and end of treatment and change in GFR per year of follow‐up (mL/min/y)
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Hypoglycaemia defined as:
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Minor hypoglycaemia
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Major hypoglycaemia
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Serious or severe hypoglycaemia.
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Glycaemic control (%HbA1c) at end of treatment or change from beginning to end of treatment and hypoglycaemia (as a dichotomous outcome) defined according to the definitions of individual studies
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Lipid profile (low density lipoprotein (LDL), high density lipoprotein (HDL), total cholesterol, triglycerides) at end of treatment and change from beginning to end of treatment.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Kidney and Transplant Specialised Register up to 31 March 2017 through contact with the Information Specialist using search terms relevant to this review. The Cochrane Kidney and Transplant Specialised Register contains studies identified from several sources.
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Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
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Weekly searches of MEDLINE OVID SP
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Handsearching of kidney‐related journals and the proceedings of major kidney conferences
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Searching of the current year of EMBASE OVID SP
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Weekly current awareness alerts for selected kidney and transplant journals
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Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about Cochrane Kidney and Transplant.
See Appendix 1 for search terms used in strategies for this review.
Searching other resources
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Reference lists of nephrology textbooks, review articles and relevant studies.
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Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.
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Conference proceedings from nephrology meetings.
Data collection and analysis
Selection of studies
The search strategy was used to obtain titles and abstracts of studies that might be relevant to the review. The titles and abstracts were screened independently by two authors, who discarded studies that were not applicable; however, studies and reviews that might include relevant data or information on studies were retained initially. Two authors independently assessed retrieved abstracts, and if necessary the full text, of these studies to determine which studies satisfied the inclusion criteria. Disagreements in the adjudication of eligible studies was resolved by consensus and discussion with a third author.
Data extraction and management
Data extraction was carried out independently by two authors using standard electronic data extraction forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was included. Where relevant outcomes are only published in earlier versions these data were used. Any discrepancy between published versions was highlighted. Disagreements in data extraction were resolved by consultation with all authors.
Assessment of risk of bias in included studies
The following items were independently assessed by two authors using the Cochrane risk of bias assessment tool (Higgins 2011) (seeAppendix 2).
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Was there adequate sequence generation (selection bias)?
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Was allocation adequately concealed (selection bias)?
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Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
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Participants and personnel
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Outcome assessors
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Were incomplete outcome data adequately addressed (attrition bias)?
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Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
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Was the study apparently free of other problems that could put it at a risk of bias?
Measures of treatment effect
For dichotomous outcomes (doubling of SCr, ESKD, death (any cause), sudden death, death (due to cardiovascular causes), non‐fatal cardiovascular events (myocardial infarction and stroke), onset of microalbuminuria, progression of albuminuria or proteinuria, regression to normoalbuminuria, regression to microalbuminuria, or regression to normoalbuminuria, or adverse effects including hypoglycaemia, the treatment effects were expressed as risk ratios (RR) together with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (urinary albumin excretion, urinary ACR, BP, SCr, CrCl, GFR), the mean difference (MD) was used, or the standardised mean difference (SMD) if different scales were used.
Unit of analysis issues
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Cluster RCTs: we considered cluster studies if they had been appropriately analysed taking into account intra‐class correlation coefficients and relevant data were documented in the report, however, no cluster RCTs were eligible for inclusion
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Cross‐over studies: no cross‐over studies were eligible for inclusion
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Studies with multiple treatment groups: studies in which there were more than two treatment arms, data for dichotomous outcomes were combined according to treatment intervention to avoid double‐counting of information.
Dealing with missing data
No correspondence was sought from investigators of eligible studies.
Assessment of heterogeneity
We first assessed the heterogeneity by visual inspection of the forest plot. Heterogeneity was then analysed using a Chi2 test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I2 test (Higgins 2003). A guide to the interpretation of I2 values is as follows.
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0% to 40%: might not be important
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30% to 60%: may represent moderate heterogeneity
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50% to 90%: may represent substantial heterogeneity
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75% to 100%: considerable heterogeneity.
The importance of the observed value of I2 depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P‐value from the Chi2 test, or a confidence interval for I2) (Higgins 2011).
Assessment of reporting biases
We generated funnel plots to assess for evidence of small‐study effects for outcomes in which there were data for nine or more studies (Higgins 2011).
Data synthesis
Data were pooled using random‐effects meta‐analysis.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis were prespecified to explore possible sources of heterogeneity (e.g. participants, interventions, and study quality). We assessed for evidence of different treatment effects based on the following characteristics:
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Age
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GFR (≥ 90 mL/min/1.73 m2 versus < 90 mL/min/1.73 m2)
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Duration of follow‐up (≥ 60 months versus < 60 months)
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Allocation concealment (low versus unclear risk)
Sensitivity analysis
We planned sensitivity analyses to explore the influence of the following factors on effect size, although insufficient data were available to complete such analyses.
'Summary of findings' tables
We presented the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schünemann 2011a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schünemann 2011b). We presented the following outcomes in the 'Summary of findings' tables.
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Doubling of SCr
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ESKD
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Sudden death
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All‐cause mortality
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Cardiovascular mortality
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Non‐fatal myocardial infarction
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Onset microalbuminuria
Results
Description of studies
Results of the search
The electronic search strategy identified 3348 unique citations. After title and abstract review 3140 records were excluded (not randomised, wrong population, wrong intervention). Of the remaining 208 records, we identified 18 studies; 14 included studies (204 records) (ACCORD Study 2007; ADVANCE Study 2001; Ciavarella 1985; DCCT 1986; Feldt‐Rasmussen 1986; KUMAMOTO Study 1995; MEMO Study 2011; OSLO Study 1986; SDIS Study 1988; STENO‐2 Study 1999; STENO Study 1982; UKPDS Study 1991; VA‐CSDM Study 1992; VADT Study 2003), and four excluded studies (four records) (Christiansen 1987; Holman 1983; Kawamori 1991; Wiseman 1985) (Figure 1).
Study flow diagram
Included studies
The 14 included studies enrolled 29,319 participants from Europe and USA published between 1982 and 2011 were included in the systematic review and 11 studies involving 29,141 participants could be included in our meta‐analysis (Characteristics of included studies). Three studies were not included in meta‐analyses as outcome data were not reported in a format that could be extracted for analysis (KUMAMOTO Study 1995; OSLO Study 1986; STENO Study 1982).
The mean duration of follow‐up in included studies was 56.7 months (ranging from 6 to 120 months).
There were four studies involving 1589 people with type 1 diabetes (Ciavarella 1985; DCCT 1986; Feldt‐Rasmussen 1986; SDIS Study 1988), eight studies involving 27,654 people with type 2 diabetes (ACCORD Study 2007; ADVANCE Study 2001; KUMAMOTO Study 1995; MEMO Study 2011; STENO‐2 Study 1999; UKPDS Study 1991; VA‐CSDM Study 1992; VADT Study 2003), and two studies involving 1665 people who had insulin‐dependent diabetes (OSLO Study 1986; STENO Study 1982).
The average age of participants was highly variable (ranging between 18 and 66 years). Of the 11 studies contributing outcome data, one study (190 participants) involved people with stage 2 CKD (eGFR 60 to 90 mL/min) (MEMO Study 2011), and five studies (11,990 participants) reported treatment in people with stage 1 CKD (eGFR > 90 mL/min/1.73 m2) (ACCORD Study 2007; DCCT 1986; Feldt‐Rasmussen 1986; SDIS Study 1988; STENO‐2 Study 1999). In the remaining studies, the level of kidney function was not specified.
Among studies included in our meta‐analyses, five (ACCORD Study 2007; Feldt‐Rasmussen 1986; SDIS Study 1988; VA‐CSDM Study 1992; VADT Study 2003) compared conventional versus intensive (continuous) therapy (12,333 participants); two studies (MEMO Study 2011; STENO‐2 Study 1999) compared standard care within general practice with intensive multifactorial intervention with behaviour modification or a structured education program (350 participants); two studies (Ciavarella 1985; DCCT 1986) compared one or two daily insulin injections versus three or more or continuous injections (1,451 participants); one study (UKPDS Study 1991) compared conventional therapy, primarily with diet alone, versus intensive therapy with sulphonylurea or metformin (3,867 participants) and one study (ADVANCE Study 2001) compared standard glucose control (with target HbA1c levels defined on the basis of local guidelines) versus intensive glucose control, defined as the use of gliclazide plus other drugs (11,140 participants) to target HbA1c ≤ 6.5%.
A detailed description of the glucose targets to which participants were randomly allocated is provided in Table 1.
| Study | Tight control | Non‐tight control | ||||||
| Treatment | Definition | Cut point | Achieved HbA1c (%)* | Treatment | Definition | Cut point | Achieved HbA1c (%)* | |
| Intensive therapy | Target HbA1c < 6.0% | HbA1c < 6.0% | 7.2 (6.6 to 7.9) | Conventional therapy | HbA1c: 7.0% to 7.9% | HbA1c: 7.0% to 7.9% | 7.6 (7 to 8.3) | |
| Intensive with gliclazide ± metformin, thiazolidinediones, acarbose or insulin | Target HbA1c≤ 6.5% | HbA1C ≤ 6.5% | 6.53 ± 0.91 | Conventional with sulphonylurea other than gliclazide | HbA1c levels defined by local guidelines | Local target | 7.30 ± 1.26 | |
| Insulin infusion (SC) | NR | NR | 9 ± 0.7 | 1 or 2 or 3 daily insulin injections | NR | NR | 11.4 ± 0.8 | |
| 3 or more daily insulin injections or insulin infusion (SC) | prePBG 3.9 to 6.7 mmol/L postPBG < 10 mmol/L HbA1c < 6.05% | prePBG 3.9 to 6.7 mmol/L postPBG < 10 mmol/L HbA1c < 6.05% | 7.2 ± NR | 1 or 2 daily insulin injections | No glycosuria, hyperglycaemia and ketonuria | No glycosuria hyperglycaemia and ketonuria | 9.1 ± NR | |
| Insulin infusion (SC) | FBG levels 5 to 10 mmol/L postPBG morning 4 to 7 mmol/L Avoiding blood glucose levels < 3 mmol/L | FPG 5 to 10 mmol/L postPBG 4 to 7 mmol/L BG > 3 mmol/L | 7.2 (5.9 to 8.8) | Conventional insulin therapy | PostPBG <15 mmol/L Glucose excretion < 20 g/24h | PostPBG < 15 mmol/L Glucose excretion < 20 g/24h | 8.6 (7.2 to 13.3) | |
| 3 or more daily insulin injections | Glycaemic control as close to the FBG < 7.78 mmol/L HbA1c < 7.0% | FBG < 7.78 mmol/L HbA1c < 7.0% | 7.2 ± 1 | 1 or 2 daily injections of intermediate‐acting insulin | glycaemic control as close to FBG < 7.78 mmol/L | FPG < 7.78 mmol/L | 9.4 ± 1.3 | |
| Intensive care + structured education program | HbA1c ≤ 6.5% | HbA1c ≤ 6.5% | 8 ± 1.6 | Standard care by general practitioner | HbA1c ≤ 6.5% | HbA1c ≤ 6.5% | 7.5 ± 1.4 | |
| 3 or more daily insulin injections or insulin infusion (SC) | NR | NR | NR | 2 daily mixed insulin injections | NR | NR | NR | |
| Intensive therapy | NR | NR | 7.1 ± 0.7 | Conventional therapy | NR | NR | 8.5 ± 0.7 | |
| Intensive multifactorial intervention with behaviour modification | HbA1c < 6.5% | HbA1c < 6.5% | NR | Standard care by general practitioner | HbA1c < 7.5% | HbA1c < 7.5% | NR | |
| Insulin infusion (SC) | PostPBG < 9 mmol/L No glycosuria | PostPBG < 9 mmol/L No glycosuria | 6.7 ± 1 | 1 or more daily injections of insulin | PostPBG <15 mmol/L Glucose excretion < 20 g/24h | PostPBG < 15mmol/L Glucose excretion < 20 g/24h | 8 ± 1.2 | |
| Intensive with metformin or sulphonylurea ± metformin or insulin | FPG < 6 mmol/L In insulin‐treated patients, pre‐meal glucose concentrations 4 to 7 mmol/L | FPG < 6 mmol/L prePBG 4 to 7 mmol/L | 7 (6.2 to 8.2) | Conventional with diet or metformin ± sulphonylurea or sulphonylurea ± metformin or insulin | Maintain FPG < 15 mmol/L without symptoms of hyperglycaemia | FPG < 15 mmol/L | 7.9 (6.9 to 8.8) | |
| Intensive therapy | HbA1c as close to the normal range as possible (5.1 ± 1% (mean ± 2 SD)) Normal mean FSG 4.44 to 6.38 mmol/L Other prePBG < 7.22 mmol/L | HbA1c 5.1% + 1 FBG 4.44 to 6.38 mmol/L prePBG < 7.22 mmol/L | 7.1 ± 0.1 | Conventional therapy | Avoid diabetic symptoms, excessive glycosuria, or overt hypoglycaemia | No diabetes, glycosuria or hypoglycaemia | 9.1 ± NR | |
| Intensive with maximal OHA doses ± insulin | Aiming for HbA1c ≤ 6% A priority is to avoid hypoglycaemia | HbA1c ≤ 6.0% No hypoglycaemia | 6.9 (NR) | Conventional with half the maximal OHA doses ± insulin | Avoidance of deterioration of HbA1c 8% to 9% and preventing symptoms of glycosuria, hypoglycaemia, and ketonuria | HbA1c 8% to 9% No glycosuria, hyperglycaemia and ketonuria | 8.4 (NR) | |
* value reported as mean ± SD or median (range)
FBG ‐ fasting blood glucose; HbA1c ‐ glycated haemoglobin; NR: not reported; PBG ‐ prandial blood glucose; SC‐ subcutaneous
Excluded studies
Four studies that were initially selected after title and abstract review were ineligible after full‐text review because of one of the following reasons: not assessing the outcome of interest (Christiansen 1987; Wiseman 1985), not targeting HbA1c less than 7% (two studies: Holman 1983; Kawamori 1991) (Characteristics of excluded studies).
Risk of bias in included studies
The risks of bias are summarised in and Figure 2 and Figure 3. See also Characteristics of included studies for details for each study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Sequence generation
Eight studies (57%) reported low risk methods for generation of the random sequence (ACCORD Study 2007; ADVANCE Study 2001; DCCT 1986; OSLO Study 1986; STENO‐2 Study 1999; UKPDS Study 1991; VADT Study 2003; VA‐CSDM Study 1992). There was insufficient information to determine sequence generation in the remaining six studies (43%) and these were judged to have unclear risk of bias.
Allocation concealment
Seven studies (50%) reported adequate methods for allocation concealment (low risk of bias) (ADVANCE Study 2001; DCCT 1986; SDIS Study 1988; STENO‐2 Study 1999; UKPDS Study 1991; VA‐CSDM Study 1992; VADT Study 2003). There was insufficient information to determine methods of allocation concealment in the remaining seven studies (50%) and these were judged to have unclear risk of bias.
Blinding
Performance bias
Two studies (14%) reported that participants and investigators were masked to treatment (ADVANCE Study 2001; DCCT 1986), three studies (21%) were open‐label and so were considered at high risk of bias (ACCORD Study 2007; STENO‐2 Study 1999; VADT Study 2003), and the remaining nine studies (65%) did not provide sufficient information to enable assessment (unclear).
Detection bias
Seven studies (50%) reported adequate methods of masking outcome assessment (ACCORD Study 2007; ADVANCE Study 2001; DCCT 1986; MEMO Study 2011; STENO‐2 Study 1999; VADT Study 2003; VA‐CSDM Study 1992); the remainder did not provide sufficient information and where judged to have unclear risk of bias.
Incomplete outcome data
Nine studies (64%) met criteria for low risk of bias (fewer than 10% missing from follow‐up analyses and balanced numbers across intervention groups with similar reasons for loss to follow‐up) of incomplete outcome data bias (ACCORD Study 2007; ADVANCE Study 2001; DCCT 1986; KUMAMOTO Study 1995; MEMO Study 2011; SDIS Study 1988; STENO Study 1982; UKPDS Study 1991; VA‐CSDM Study 1992), two studies (14%) was at high risk of bias (Ciavarella 1985; Feldt‐Rasmussen 1986), and the remaining three studies (21%) did not provide sufficient information and were judged to unclear risk of bias.
Selective reporting
Eleven studies (89%) reported all expected outcomes and were judged to be at low risk of bias (ACCORD Study 2007; ADVANCE Study 2001; Ciavarella 1985DCCT 1986; Feldt‐Rasmussen 1986; MEMO Study 2011; SDIS Study 1988; STENO‐2 Study 1999; UKPDS Study 1991; VA‐CSDM Study 1992; VADT Study 2003). Three studies (21%) were not able to be meta‐analysed and were judged to be at high risk of bias (KUMAMOTO Study 1995; OSLO Study 1986; STENO Study 1982).
Other potential sources of bias
There were three studies (21%) that reported the sponsor was involved in authorship of the study report or in data management or analysis (ACCORD Study 2007; STENO‐2 Study 1999; VADT Study 2003).
Effects of interventions
The summary of findings Table for the main comparison for the main comparison provides overall estimates and our confidence in treatment effects for the key (preventing the onset and progression of kidney disease) and safety (cardiovascular events or death) outcomes.
Primary outcomes
Doubling of serum creatinine
Tight glycaemic control may make little or no difference to doubling of SCr compared with standard control (Analysis 1.1 (4 studies, 26,874 participants): RR 0.84, 95% CI 0.64 to 1.11; I2= 73%; low certainty evidence).
End‐stage kidney disease
Tight glycaemic control may make little or no difference to patients developing ESKD compared with standard glycaemic control (Analysis 1.2 (4 studies, 23,332 participants): RR 0.62, 95% CI 0.34 to 1.12; I2= 52%; low certainty evidence).
Death (from any cause, cardiovascular causes, or sudden)
Tight glycaemic control probably makes little or no difference to all‐cause mortality (Analysis 1.3 (9 studies, 29,094 participants): RR 0.99, 95% CI 0.86 to 1.13; I2= 50%; moderate certainty evidence), cardiovascular mortality (Analysis 1.4 (6 studies, 23,673 participants): RR 1.19, 95% CI 0.73 to 1.92; I2= 85%; low certainty evidence) and sudden death (Analysis 1.5 (4 studies, 5913 participants): RR 0.82, 95% CI 0.26 to 2.57; I2= 85%; very low certainty evidence) compared with standard glycaemic control.
Fatal and non‐fatal cardiovascular events including myocardial infarction and stroke
Tight glycaemic control may make little or no difference to fatal myocardial infarction (Analysis 1.6 (3 studies, 14,220 participants): RR 1.11, 95% CI 0.76 to 1.62; I2= 24%) and stroke (Analysis 1.7 (3 studies, 15,909 participants): RR 1.11, 95% CI 0.71 to 1.75; I2= 0%) compared with standard glycaemic control.
Tight glycaemic control probably reduces non‐fatal myocardial infarction (Analysis 1.8 (5 studies, 25,596 participants): RR 0.82, 95% CI 0.67 to 0.99; I2= 46%, moderate certainty evidence), but probably makes little or no difference to the risk of non‐fatal stroke (Analysis 1.9 (5 studies, 25,596 participants): RR 0.94, 95% CI 0.68 to 1.31; I2= 64%) compared with standard glycaemic control.
Secondary outcomes
Onset, progression or regression of microalbuminuria
Tight glycaemic control probably reduces the risk of onset of microalbuminuria compared with standard control (Analysis 1.10 (4 studies, 19,846 participants): RR 0.82, 95% CI 0.71 to 0.93; I2= 61%, moderate certainty evidence). Similarly, tight glycaemic control probably decreases the risk of progression of microalbuminuria (Analysis 1.11 (5 studies, 13,266 participants): RR 0.59, 95% CI 0.38 to 0.93; I2= 75%, moderate certainty evidence) compared to standard control.
DCCT 1986 reported tight glycaemic control may make little or no difference to regression of albuminuria compared with conventional control (Analysis 1.12, (1 study, 73 participants): RR 1.18, 95% CI 0.78 to 1.78).
End of treatment urinary albumin‐creatinine ratio
This outcome was not reported in any of the included studies.
End of treatment serum creatinine
Tight glycaemic control had may make little of no difference to SCr compared with conventional glycaemic control (Analysis 1.13 (4 studies, 12718 participants): MD 0.96 µmol/L, 95% CI ‐0.42 to 2.34; I2 = 0%).
End of treatment creatinine clearance or glomerular filtration rate
Tight glycaemic control may make little of no difference to GFR compared with conventional glycaemic control (Analysis 1.14 (3 studies, 164 participants): MD ‐4.86 mL/min, 95% CI ‐15.69 to 5.97; I2 = 31%).
Hypoglycaemia
Data on side effects related to metformin, sulphonylureas, glitazones, meglitinides, alpha‐glucosidase, exenatide, liraglutide and insulin were not reported. The narrative findings for hypoglycaemia are shown in Table 2 as these were reported in heterogeneous ways that precluded meta‐analysis.
| Study ID | Intervention | Control | Statistical inference |
| 3,1 severe hypoglycaemia /100 patient‐year (830 patient, 16.2%) 1 hypoglycaemia‐related death | 1 severe hypoglycaemia/100 patient‐year (261 patient, 5.1%) 1 hypoglycaemia‐related death | P < 0.001 | |
| 0.7 severe hypoglycaemia/100 patient‐year (150 patients, 2.7%) 120 minor hypoglycaemia/100 patient‐year | 0.4 severe hypoglycaemia/100 patient‐year (81 patients, 1.5%) 90 minor hypoglycaemia/100 patient‐year | P < 0.001 | |
| 549 (77%) severe hypoglycaemia | 165 (23%) severe hypoglycaemia | P < 0.001 | |
| 42.4% mild hypoglycaemia 11.2% moderate hypoglycaemia 0% severe hypoglycaemia | 32.5% mild hypoglycaemia 29% moderate hypoglycaemia 6.3% severe hypoglycaemia | P = 0.52 P = 0.001 P = 0.07 | |
| 1.1 serious hypoglycaemia/patient‐year (80%) | 0.4 serious hypoglycaemia/patient‐year (58%) | P < 0.5 | |
| 42 patients ≥1 minor hypoglycaemia 5 patients ≥1 major hypoglycaemia | 39 patients ≥1 minor hypoglycaemia 12 patients ≥1 major hypoglycaemia | P = 0.50 P = 0.12 | |
| 1566 any hypoglycaemia/100 patient‐year 12 major hypoglycaemia/100 patient‐year | 432 any hypoglycaemia/100 patient‐year 4 major hypoglycaemia/100 patient‐year | P < 0.001 |
End of treatment glycaemic control (HbA1c)
Glycaemic control at the end of treatment was probably reduced with intensive therapy compared with standard therapy (Analysis 1.15 (5 studies, 11583 participants): MD ‐1.38%, 95% CI ‐1.93 to ‐0.82; I2 = 96%).
Lipid profile
This outcome was not reported in any of the included studies.
Subgroup and sensitivity analysis
Subgroup analysis were run to explore potential different effects of the treatment related to age (greater or less than 60 years old), allocation concealment (unclear versus low risk), study duration (greater or less than 60 months) and GFR (greater or less than 90 mL/min/1.72m2). There was no evidence of a difference between the subgroups for any of the outcomes included in the subgroup analysis related to age, allocation concealment, or GFR.
We found that in studies with a duration of less than 60 months, the risk of cardiovascular (Analysis 2.3.1: RR 1.73, 95% CI 1.04 to 2.90; test for subgroup differences: Chi2 = 5.49, (P = 0.02), I2 = 81.8%) and all‐cause mortality (Analysis 2.7.1: RR 1.18, 95% CI 1.03 to 1.36; test for subgroup differences: Chi2 = 5.74, (P = 0.02), I2 = 82.6%) was statistically significant.
We did sensitivity analysis excluding STENO‐2 Study 1999 to check for the robustness of results as this study evaluated a multifactorial intervention including glucose targets but also including cholesterol lowering, lifestyle management, BP control. This did not alter the findings for any outcome, which remained consistent with overall findings with all studies included (specifically for the primary outcomes ESKD: RR 0.66, 95% CI 0.36 to 1.19; all‐cause mortality: RR 1.03, 95% CI 0.93 to 1.14; cardiovascular mortality: RR 1.21, 95% CI 0.71 to 2.07). We did an additional sensitivity analysis restricted to studies involving people with type 2 diabetes. In these sensitivity analyses all treatment effects were not substantively different from the principal analyses including all study populations.
We generated a funnel plot for the outcome of all‐cause mortality to assess for evidence of small‐study effects (Figure 4). There was no evidence of small‐study effects in this meta‐analysis. There were insufficient observations in the meta‐analyses for all other outcomes (fewer than 9 to 10 studies) to permit funnel plot generation.
Funnel plot of comparison: 1 Tight versus non‐tight glycaemic control, outcome: 1.3 All‐cause mortality.
Discussion
Summary of main results
This review summarises 14 studies involving 29,319 people with diabetes that evaluated the effects of tight versus standard glycaemic control. Studies included people with both type 1 and type 2 diabetes and people with a range of kidney function. Studies lasted approximately five years on average, although this ranged between six months and 10 years. Intensive glycaemic control was achieved by multifactorial behavioural and education interventions in general practice, different insulin regimens, or intensive oral hypoglycaemic medication.
Although glucose‐lowering strategies to achieve tighter glucose control led to people experiencing better glycaemic control (reducing their HbA1C by 1.24% on average), this did not result in clinically important reductions in experiences of kidney failure (doubling of SCr or ESKD), or premature mortality or major cardiovascular complications. While treatment might have reduce the risks of non‐fatal myocardial infarction proportionally by 18%, in absolute terms, out of 1,000 people with diabetes receiving interventions to achieve tight glycaemic control for four to eight years might lead to between zero and two people avoiding complications (each of mortality, cardiovascular death, sudden death, ESKD, doubling of SCr, nonfatal myocardial infarction). People who were allocated to tight glycaemic control had measurable reductions in their risk of developing new microalbuminuria or progression to higher levels of microalbuminuria (proportional risk reductions of 18% and 41% respectively), but as these are surrogate measures of kidney injury, these treatment effects are of uncertain future clinical significance for these treated patients.
It is possible that tight glycaemic control might have different effects in different practice settings. We therefore examined whether treatment effects were different based on age, duration of treatment, the baseline level of kidney function and the methodological quality of the study. There was no discernible effect of age, kidney function or study methodology on estimated treatment effects. A longer duration of treatment was associated with lower risks of all‐cause mortality and cardiovascular death, although an in‐depth exploration of the mechanisms by which longer treatment might work is beyond the scope of this review and might be confounded by other factors such as study quality or participant characteristics.
In general, adverse events were incompletely reports and due to limitations in the evidence because of inconsistent treatment effects measured by different studies, and limitations in studies based on the reporting of methods, the confidence in the evidence for most outcomes was downgraded from high confidence, meaning that future studies might have different results and lead to changing in our knowledge about the impact of glucose control for people with diabetes.
Overall, this evidence summary does not support the use of tighter glucose control to offer people with diabetes a lower risk of premature mortality or protection against kidney failure. While tighter glucose control does appear to reduce some biochemical markers of kidney disease, the clinical relevance of these endpoints is uncertain and there is no evidence that these treatment effects translate to a reduction in needing dialysis or kidney transplantation in the long‐term based on the current trial evidence. People may reasonably wish to consider treatment that targets lower blood sugars with the understanding that the potentially harmful consequences of this approach are poorly measured and the absolute clinical treatment benefits are probably small during treatment on average of five to eight years.
Overall completeness and applicability of evidence
Although this review could include studies with a relatively large number of people, there were few studies overall measuring treatment impact on kidney failure and cardiovascular complications. The imprecision in our estimates of treatment effect reduced our confidence in the results, meaning that future studies might provide different results and change our knowledge about the effects of tight glucose control on kidney function. Notably, most of the studies included in this meta‐analysis have involved patients with type 2 diabetes, suggesting the results of this analysis may not be applicable to the management of type 1 diabetes.
Although kidney failure requiring dialysis or kidney transplantation is a common complication of diabetes in the long‐term, ESKD was a rare complication for people treated in the included studies, even over treatment lasting 5 to 10 years. Despite over 12,000 people included in available studies, fewer than 2% experienced kidney failure. As kidney failure is a rare outcome, it is very unlikely that future studies will be sufficiently prioritised or statistically large enough to determine whether glycaemic control can prevent long‐term kidney failure. Current studies have measured treatment impact on levels of kidney albumin excretion, a biochemical marker of kidney injury associated with higher risks of kidney failure and cardiovascular complications, however it is unclear whether drug‐related reductions in albuminuria necessarily translate into prevention of kidney failure with treatment.
Despite modest average reductions in the risk of nonfatal myocardial infarction for people allocated to tight glycaemic control, the absolute number of people avoiding this complication for 1000 people treated is very small and of uncertain clinical importance. In light of the small absolute benefits of tight glucose control, it is important to have a full understanding of treatment‐related harms. However, existing studies infrequently reported harms, including serious hypoglycaemia, such that people considering treatment to stricter glycaemic targets cannot reasonably balance the advantages and disadvantages of treatment to their health in both the short and long‐term.
Quality of the evidence
We graded our confidence in the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Guyatt 2011), which considers study limitations, imprecision, indirectness, inconsistency and publication bias. Overall, most studies had overall unclear risks of bias for most domains of study reporting assessed. Estimated effects on efficacy and safety outcomes were frequently imprecise with confidence intervals that were consistent with both considerable benefit or harm. The drop‐out rate in 10/14 studies was <10%. Moderate heterogeneity in treatment estimates for tight compared with non‐tight glucose control were present in analyses for sudden death, cardiovascular mortality, doubling SCr and onset of microalbuminuria.
Overall, based on important limitations, our confidence in the evidence varied between very low and moderate for most outcomes, indicating that future research might have an important impact on the treatment effects observed and may change the estimated treatment impact. We carried out sensitivity analyses to explore the effect of study quality (allocation concealment) in order to assess whether this made any difference to the results. There was no strong evidence that different clinical settings and design modified the results, although the statistical power of these analyses was low and these results are hypothesis‐generating. There was no strong evidence of different treatment effects from smaller studies, though this is difficult to detect with the number of studies in this review.
Potential biases in the review process
We did this review according to a prespecified protocol and using a highly sensitive search strategy without date or language restrictions. We considered the evidence in the context of study methodological limitations using the GRADE approach. We carried out sensitivity analyses to assess the impact of study quality and other participant and study characteristics on the results.
Despite these processes, the study has limitations which need to be considered when interpreting the results, principally related to the primary studies in the review. Many of the studies did not report methodological elements in sufficient detail to ascertain risks of bias, which reduced our confidence in the results. The number of people in the studies who reached ESKD was very small, leading to considerable uncertainty for this outcome. Further studies are unlikely to address this issue meaningfully as very large numbers of people will need to be included in studies. As a consequence, many of the studies reported surrogate measures of outcomes for kidney function including albuminuria. While statistical effects were observed, the clinical value of these results remains uncertain. In future, standardised outcomes of most relevance to patients and health professionals will help the design of studies that measure outcomes that are clinically important.
Agreements and disagreements with other studies or reviews
This review finds similar results to a previous similar systematic review of intensive glycaemic control in people with type 2 diabetes and extends analyses of that review to also include kidney function outcomes. As was observed in this review, a previous review did not find any differences in risks of death (due to any cause or cardiovascular‐related) for people treated with tight glycaemic control and there was insufficient information in accrued studies published in 2011 to show conclusive benefits on risks of cardiac complications. When asked, patients foster supportive collaborative relationships to balance their need for support and advice with the need to maintain autonomy and self‐esteem. In this context, this review might help discussions between patients and health practitioners to personalise glycaemic targets to balance the small potential benefits with the uncertain and potentially important hazards of hypoglycaemia (Paterson 1998).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Funnel plot of comparison: 1 Tight versus non‐tight glycaemic control, outcome: 1.3 All‐cause mortality.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 1 Doubling serum creatinine.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 2 Development ESKD.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 3 All‐cause mortality.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 4 Cardiovascular mortality.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 5 Sudden death.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 6 Fatal myocardial infarction.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 7 Fatal stroke.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 8 Non‐fatal myocardial infarction.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 9 Non‐fatal stroke.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 10 Onset microalbuminuria.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 11 Progression of microalbuminuria.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 12 Regression of albuminuria.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 13 Serum creatinine.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 14 Glomerular filtration rate.
Comparison 1 Tight versus non‐tight glycaemic control, Outcome 15 HbA1c.
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 1 Cardiovascular mortality (age).
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 2 Cardiovascular mortality (allocation concealment).
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 3 Cardiovascular mortality (duration of treatment).
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 4 Cardiovascular mortality (GFR).
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 5 All‐cause mortality (age).
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 6 All‐cause mortality (allocation concealment).
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 7 All‐cause mortality (duration of treatment).
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 8 All‐cause mortality (GFR).
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 9 Non‐fatal myocardial infarction (age).
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 10 Non‐fatal myocardial infarction (allocation concealment).
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 11 Non‐fatal myocardial infarction (duration of treatment).
Comparison 2 Tight versus non‐tight glycaemic control (subgroup analyses), Outcome 12 Non‐fatal myocardial infarction (GFR).
| Tight glycaemic control compared with non‐tight control for preventing DKD and its progression | ||||||
| Patient or population: patients with diabetes Intervention: tight glycaemic control Comparison: non‐tight glycaemic control | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Confidence of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Non‐tight control | Tight control | |||||
| Doubling serum creatinine 8.3 years | 39 per 1000 | 33 per 1000 (24.95 to 43.29) NNT: 167 | RR 0.84 (0.64 to 1.11) | 26,874 (4) | ⊕⊕⊝⊝ | Imprecision (‐1) Heterogeneity (‐1) |
| ESKD 5.9 years | 3 per 1000 | 2 per 1000 (1.02 to 3.36) NNT: 1000 | RR 0.62 (0.34 to 1.12) | 23,332 (4) | ⊕⊕⊝⊝ | Imprecision (‐1) Heterogeneity (‐1) |
| Sudden death 4.6 years | 2 per 1000 | 2 per 1000 (0.52 to 5.14) NNT: 0 | RR 0.82 (0.26 to 2.57) | 5,913 (4) | ⊕⊝⊝⊝ | Study limitation (‐1) Imprecision (‐1) Heterogeneity (‐1) |
| All‐cause mortality 5.6 years | 16 per 1000 | 16 per 1000 (13.76‐18.08) NNT: 0 | RR 0.99 (0.86 to 1.13) | 29,094 (9) | ⊕⊕⊕⊝ | Imprecision (‐1) |
| Cardiovascular mortality 4.4 years | 9 per 1000 | 11 per 1000 (6.57 to 17.28) NNH: 500 | RR 1.19 (0.73 to 1.92) | 23,673 (6) | ⊕⊕⊝⊝ | Imprecision (‐1) Heterogeneity (‐1) |
| Non‐fatal myocardial infarction 5.6 years | 8 per 1000 | 7 per 1000 (5.36 to 7.92) NNT: 1000 | RR 0.82 (0.67 to 0.99) | 25,596 (5) | ⊕⊕⊕⊝ | Study limitation (‐1) |
| Onset microalbuminuria 5.4 years | 46 per 1000 | 39 per 1000 (35.42 to 43.24) NNT: 143 | RR 0.85 (0.77 to 0.94) | 19,933 (4) | ⊕⊕⊕⊝ | Heterogeneity (‐1) |
| Progression of microalbuminuria 5.8 years | 4 per 1000 | 2 per 1000 (1.52 to 3.72) NNT: 500 | RR 0.59 (0.38 to 0.93) | 13,266 (5) | ⊕⊕⊕⊝ | Heterogeneity (‐1) |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is calculated from data in the meta‐analyses. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). We did not downgrade for reason of publication bias as insufficient studies contributed to treatment estimates to draw meaningful conclusions | ||||||
| GRADE Working Group grades of evidence | ||||||
| ESKD ‐ end‐stage kidney disease | ||||||
| Study | Tight control | Non‐tight control | ||||||
| Treatment | Definition | Cut point | Achieved HbA1c (%)* | Treatment | Definition | Cut point | Achieved HbA1c (%)* | |
| Intensive therapy | Target HbA1c < 6.0% | HbA1c < 6.0% | 7.2 (6.6 to 7.9) | Conventional therapy | HbA1c: 7.0% to 7.9% | HbA1c: 7.0% to 7.9% | 7.6 (7 to 8.3) | |
| Intensive with gliclazide ± metformin, thiazolidinediones, acarbose or insulin | Target HbA1c≤ 6.5% | HbA1C ≤ 6.5% | 6.53 ± 0.91 | Conventional with sulphonylurea other than gliclazide | HbA1c levels defined by local guidelines | Local target | 7.30 ± 1.26 | |
| Insulin infusion (SC) | NR | NR | 9 ± 0.7 | 1 or 2 or 3 daily insulin injections | NR | NR | 11.4 ± 0.8 | |
| 3 or more daily insulin injections or insulin infusion (SC) | prePBG 3.9 to 6.7 mmol/L postPBG < 10 mmol/L HbA1c < 6.05% | prePBG 3.9 to 6.7 mmol/L postPBG < 10 mmol/L HbA1c < 6.05% | 7.2 ± NR | 1 or 2 daily insulin injections | No glycosuria, hyperglycaemia and ketonuria | No glycosuria hyperglycaemia and ketonuria | 9.1 ± NR | |
| Insulin infusion (SC) | FBG levels 5 to 10 mmol/L postPBG morning 4 to 7 mmol/L Avoiding blood glucose levels < 3 mmol/L | FPG 5 to 10 mmol/L postPBG 4 to 7 mmol/L BG > 3 mmol/L | 7.2 (5.9 to 8.8) | Conventional insulin therapy | PostPBG <15 mmol/L Glucose excretion < 20 g/24h | PostPBG < 15 mmol/L Glucose excretion < 20 g/24h | 8.6 (7.2 to 13.3) | |
| 3 or more daily insulin injections | Glycaemic control as close to the FBG < 7.78 mmol/L HbA1c < 7.0% | FBG < 7.78 mmol/L HbA1c < 7.0% | 7.2 ± 1 | 1 or 2 daily injections of intermediate‐acting insulin | glycaemic control as close to FBG < 7.78 mmol/L | FPG < 7.78 mmol/L | 9.4 ± 1.3 | |
| Intensive care + structured education program | HbA1c ≤ 6.5% | HbA1c ≤ 6.5% | 8 ± 1.6 | Standard care by general practitioner | HbA1c ≤ 6.5% | HbA1c ≤ 6.5% | 7.5 ± 1.4 | |
| 3 or more daily insulin injections or insulin infusion (SC) | NR | NR | NR | 2 daily mixed insulin injections | NR | NR | NR | |
| Intensive therapy | NR | NR | 7.1 ± 0.7 | Conventional therapy | NR | NR | 8.5 ± 0.7 | |
| Intensive multifactorial intervention with behaviour modification | HbA1c < 6.5% | HbA1c < 6.5% | NR | Standard care by general practitioner | HbA1c < 7.5% | HbA1c < 7.5% | NR | |
| Insulin infusion (SC) | PostPBG < 9 mmol/L No glycosuria | PostPBG < 9 mmol/L No glycosuria | 6.7 ± 1 | 1 or more daily injections of insulin | PostPBG <15 mmol/L Glucose excretion < 20 g/24h | PostPBG < 15mmol/L Glucose excretion < 20 g/24h | 8 ± 1.2 | |
| Intensive with metformin or sulphonylurea ± metformin or insulin | FPG < 6 mmol/L In insulin‐treated patients, pre‐meal glucose concentrations 4 to 7 mmol/L | FPG < 6 mmol/L prePBG 4 to 7 mmol/L | 7 (6.2 to 8.2) | Conventional with diet or metformin ± sulphonylurea or sulphonylurea ± metformin or insulin | Maintain FPG < 15 mmol/L without symptoms of hyperglycaemia | FPG < 15 mmol/L | 7.9 (6.9 to 8.8) | |
| Intensive therapy | HbA1c as close to the normal range as possible (5.1 ± 1% (mean ± 2 SD)) Normal mean FSG 4.44 to 6.38 mmol/L Other prePBG < 7.22 mmol/L | HbA1c 5.1% + 1 FBG 4.44 to 6.38 mmol/L prePBG < 7.22 mmol/L | 7.1 ± 0.1 | Conventional therapy | Avoid diabetic symptoms, excessive glycosuria, or overt hypoglycaemia | No diabetes, glycosuria or hypoglycaemia | 9.1 ± NR | |
| Intensive with maximal OHA doses ± insulin | Aiming for HbA1c ≤ 6% A priority is to avoid hypoglycaemia | HbA1c ≤ 6.0% No hypoglycaemia | 6.9 (NR) | Conventional with half the maximal OHA doses ± insulin | Avoidance of deterioration of HbA1c 8% to 9% and preventing symptoms of glycosuria, hypoglycaemia, and ketonuria | HbA1c 8% to 9% No glycosuria, hyperglycaemia and ketonuria | 8.4 (NR) | |
| * value reported as mean ± SD or median (range) FBG ‐ fasting blood glucose; HbA1c ‐ glycated haemoglobin; NR: not reported; PBG ‐ prandial blood glucose; SC‐ subcutaneous | ||||||||
| Study ID | Intervention | Control | Statistical inference |
| 3,1 severe hypoglycaemia /100 patient‐year (830 patient, 16.2%) 1 hypoglycaemia‐related death | 1 severe hypoglycaemia/100 patient‐year (261 patient, 5.1%) 1 hypoglycaemia‐related death | P < 0.001 | |
| 0.7 severe hypoglycaemia/100 patient‐year (150 patients, 2.7%) 120 minor hypoglycaemia/100 patient‐year | 0.4 severe hypoglycaemia/100 patient‐year (81 patients, 1.5%) 90 minor hypoglycaemia/100 patient‐year | P < 0.001 | |
| 549 (77%) severe hypoglycaemia | 165 (23%) severe hypoglycaemia | P < 0.001 | |
| 42.4% mild hypoglycaemia 11.2% moderate hypoglycaemia 0% severe hypoglycaemia | 32.5% mild hypoglycaemia 29% moderate hypoglycaemia 6.3% severe hypoglycaemia | P = 0.52 P = 0.001 P = 0.07 | |
| 1.1 serious hypoglycaemia/patient‐year (80%) | 0.4 serious hypoglycaemia/patient‐year (58%) | P < 0.5 | |
| 42 patients ≥1 minor hypoglycaemia 5 patients ≥1 major hypoglycaemia | 39 patients ≥1 minor hypoglycaemia 12 patients ≥1 major hypoglycaemia | P = 0.50 P = 0.12 | |
| 1566 any hypoglycaemia/100 patient‐year 12 major hypoglycaemia/100 patient‐year | 432 any hypoglycaemia/100 patient‐year 4 major hypoglycaemia/100 patient‐year | P < 0.001 |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Doubling serum creatinine Show forest plot | 4 | 26874 | Risk Ratio (IV, Random, 95% CI) | 0.84 [0.64, 1.11] |
| 2 Development ESKD Show forest plot | 4 | 23332 | Risk Ratio (IV, Random, 95% CI) | 0.62 [0.34, 1.12] |
| 3 All‐cause mortality Show forest plot | 9 | 29094 | Risk Ratio (IV, Random, 95% CI) | 0.99 [0.86, 1.13] |
| 4 Cardiovascular mortality Show forest plot | 6 | 23673 | Risk Ratio (IV, Random, 95% CI) | 1.19 [0.73, 1.92] |
| 5 Sudden death Show forest plot | 4 | 5913 | Risk Ratio (IV, Random, 95% CI) | 0.82 [0.26, 2.57] |
| 6 Fatal myocardial infarction Show forest plot | 3 | 14220 | Risk Ratio (IV, Random, 95% CI) | 1.11 [0.76, 1.62] |
| 7 Fatal stroke Show forest plot | 3 | 15909 | Risk Ratio (IV, Random, 95% CI) | 1.11 [0.71, 1.75] |
| 8 Non‐fatal myocardial infarction Show forest plot | 5 | 25596 | Risk Ratio (IV, Random, 95% CI) | 0.82 [0.67, 0.99] |
| 9 Non‐fatal stroke Show forest plot | 5 | 25596 | Risk Ratio (IV, Random, 95% CI) | 0.94 [0.68, 1.31] |
| 10 Onset microalbuminuria Show forest plot | 4 | 19933 | Risk Ratio (IV, Random, 95% CI) | 0.85 [0.77, 0.94] |
| 11 Progression of microalbuminuria Show forest plot | 5 | 13266 | Risk Ratio (IV, Random, 95% CI) | 0.59 [0.38, 0.93] |
| 12 Regression of albuminuria Show forest plot | 1 | Risk Ratio (IV, Random, 95% CI) | Totals not selected | |
| 13 Serum creatinine Show forest plot | 4 | 12718 | Mean Difference (IV, Random, 95% CI) | 0.96 [‐0.42, 2.34] |
| 14 Glomerular filtration rate Show forest plot | 3 | 164 | Mean Difference (IV, Random, 95% CI) | ‐4.86 [‐15.69, 5.96] |
| 15 HbA1c Show forest plot | 5 | 11583 | Mean Difference (IV, Random, 95% CI) | ‐1.38 [‐1.93, ‐0.82] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Cardiovascular mortality (age) Show forest plot | 6 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 1.1 < 60 years | 1 | 160 | Risk Ratio (IV, Random, 95% CI) | 1.0 [0.37, 2.72] |
| 1.2 > 60 years | 5 | 23513 | Risk Ratio (IV, Random, 95% CI) | 1.21 [0.71, 2.07] |
| 2 Cardiovascular mortality (allocation concealment) Show forest plot | 6 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 2.1 Unclear risk | 1 | 178 | Risk Ratio (IV, Random, 95% CI) | 0.75 [0.17, 3.25] |
| 2.2 Low risk | 5 | 23495 | Risk Ratio (IV, Random, 95% CI) | 1.23 [0.74, 2.06] |
| 3 Cardiovascular mortality (duration of treatment) Show forest plot | 6 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 3.1 < 60 months | 3 | 10582 | Risk Ratio (IV, Random, 95% CI) | 1.73 [1.04, 2.90] |
| 3.2 > 60 months | 3 | 13091 | Risk Ratio (IV, Random, 95% CI) | 0.91 [0.78, 1.06] |
| 4 Cardiovascular mortality (GFR) Show forest plot | 3 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 4.1 < 90 mL/min/1.73 m² | 1 | 178 | Risk Ratio (IV, Random, 95% CI) | 0.75 [0.17, 3.25] |
| 4.2 > 90 mL/min/1.73 m² | 2 | 10411 | Risk Ratio (IV, Random, 95% CI) | 1.70 [0.90, 3.21] |
| 5 All‐cause mortality (age) Show forest plot | 9 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 5.1 < 60 years | 5 | 5723 | Risk Ratio (IV, Random, 95% CI) | 0.88 [0.65, 1.21] |
| 5.2 > 60 years | 4 | 23371 | Risk Ratio (IV, Random, 95% CI) | 1.05 [0.89, 1.24] |
| 6 All‐cause mortality (allocation concealment) Show forest plot | 9 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 6.1 Unclear risk | 1 | 189 | Risk Ratio (IV, Random, 95% CI) | 0.59 [0.15, 2.41] |
| 6.2 Low risk | 8 | 28905 | Risk Ratio (IV, Random, 95% CI) | 0.99 [0.86, 1.14] |
| 7 All‐cause mortality (duration of treatment) Show forest plot | 9 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 7.1 < 60 months | 3 | 10593 | Risk Ratio (IV, Random, 95% CI) | 1.18 [1.03, 1.36] |
| 7.2 > 60 months | 6 | 18501 | Risk Ratio (IV, Random, 95% CI) | 0.94 [0.83, 1.07] |
| 8 All‐cause mortality (GFR) Show forest plot | 5 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 8.1 < 90 mL/min/1.73 m² | 1 | 189 | Risk Ratio (IV, Random, 95% CI) | 0.59 [0.15, 2.41] |
| 8.2 > 90 mL/min/1.73 m² | 4 | 11954 | Risk Ratio (IV, Random, 95% CI) | 1.01 [0.60, 1.69] |
| 9 Non‐fatal myocardial infarction (age) Show forest plot | 5 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 9.1 < 60 years | 2 | 4027 | Risk Ratio (IV, Random, 95% CI) | 0.54 [0.21, 1.44] |
| 9.2 > 60 years | 3 | 21569 | Risk Ratio (IV, Random, 95% CI) | 0.87 [0.73, 1.03] |
| 10 Non‐fatal myocardial infarction (allocation concealment) Show forest plot | 5 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 10.1 Unclear risk | 1 | 178 | Risk Ratio (IV, Random, 95% CI) | 0.33 [0.01, 8.07] |
| 10.2 Low risk | 4 | 25418 | Risk Ratio (IV, Random, 95% CI) | 0.82 [0.67, 1.01] |
| 11 Non‐fatal myocardial infarction (duration of treatment) Show forest plot | 5 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 11.1 < 60 months | 2 | 10429 | Risk Ratio (IV, Random, 95% CI) | 0.79 [0.65, 0.95] |
| 11.2 > 60 months | 3 | 15167 | Risk Ratio (IV, Random, 95% CI) | 0.80 [0.57, 1.12] |
| 12 Non‐fatal myocardial infarction (GFR) Show forest plot | 3 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 12.1 < 90 mL/min/1.73 m² | 1 | 178 | Risk Ratio (IV, Random, 95% CI) | 0.33 [0.01, 8.07] |
| 12.2 > 90 mL/min/1.73 m² | 2 | 10411 | Risk Ratio (IV, Random, 95% CI) | 0.54 [0.21, 1.39] |
