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20 September 2011
A Cochrane review of 20 randomised controlled trials (RCTs) found that intensive blood glucose control did not significantly reduce all-cause mortality or cardiovascular (CV) mortality, compared with conventional blood glucose control in people with type 2 diabetes. Intensive blood glucose control did reduce the risk of microvascular complications, but doubled the risk of severe hypoglycaemia. Results of a recent BMJ meta-analysis were similar, although in contrast to the Cochrane review, this analysis found no reduction in most microvascular outcomes with intensive blood glucose control.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
There is no argument in favour of poor blood glucose control in people with type 2 diabetes. However, the balance of risks and benefits of intensive blood glucose control need to be carefully considered on an individual patient basis. NICE guidance on type 2 diabetes should be followed and individual targets for HbA1c should be agreed with each individual patient, taking into account the patient’s own preferences for care and the balance of likely benefits and harms. A holistic approach to an individual patient’s care, deploying maximal lifestyle interventions (stopping smoking, losing weight, taking more exercise), controlling blood pressure, taking a statin, and taking metformin, seems likely to prevent more complications than a narrower focus on attempting to achieve intensive (rather than good) blood glucose control.
What is the background to this?
Four key RCTs have assessed the benefits and harms of conventional blood glucose control, compared with intensive blood glucose control in people with type 2 diabetes (UKPDS, ACCORD, ADVANCE and VADT). There have also been a number of meta-analyses, including Ray KK, et al, Kelly TN, et al, and the CONTROL meta-analysis, which have been discussed in previous MeReC Rapid Reviews. UKPDS 10-year follow-up data are also available, although there are inherent biases in observational follow-up data.
A MeReC Bulletin on type 2 diabetes has recently summarised this evidence. Intensive compared with conventional blood glucose control does have some benefits, but it also has harms. Overall, the available evidence suggests there is no significant reduction in all-cause mortality or CV mortality, a significant reduction in certain microvascular events (although the evidence is inconsistent), and an increased risk of severe hypoglycaemia with intensive, compared with conventional blood glucose control.
Another systematic review and meta-analysis has recently been conducted by Cochrane. This Cochrane review claims to be the first systematic review that includes all randomised trials assessing targeted intensive versus targeted conventional blood glucose control in people with type 2 diabetes. Previous meta-analyses reported on mortality and macrovascular outcomes, while this Cochrane review (n=29,986) also included microvascular outcomes.
What does this study claim?
This Cochrane review claims that there was no statistically significant difference between targeting intensive compared with targeting conventional blood glucose control for all-cause mortality (relative risk [RR] 1.01, 95% confidence interval [CI] 0.90 to 1.13, p=0.92, n=29,731) or CV mortality (RR 1.06, 95% CI 0.90 to 1.26, p=0.46, n=29,731) — the primary outcomes. There was also no significant reduction in other macrovascular outcomes e.g. non-fatal stroke. There was a significant reduction in microvascular outcomes e.g. amputation, retinopathy (except end-stage renal disease) and in non-fatal MI in some analyses, but a significant increase in severe hypoglycaemia (RR 2.05, 95% CI 1.39 to 3.02, p=0.0003, n=28,127). See ‘Study details – results’ for more information. The authors suggest a ‘cautious approach when reducing blood glucose and the balance of benefits and harms should be taken into account’.
How does this relate to other studies?
In addition to the studies and meta-analyses described above, another meta-analysis has recently been published in the BMJ. This analysed 13 RCTs (n=34,533) comparing intensive blood glucose lowering with standard treatment, less-intensive blood glucose lowering, or placebo. As in the Cochrane review, the authors found no significant effect on all-cause mortality or CV mortality (the primary outcomes) or any other CV outcomes e.g. stroke, with intensive compared with standard blood glucose lowering, with the exception of a reduction in non-fatal MI (RR 0.85, 99% CI 0.74 to 0.96, p<0.001). There was also an increase in the risk of severe hypoglycaemia (RR 2.33, 99% CI 1.62 to 3.36, p<0.001). However, in contrast to the Cochrane review, intensive blood glucose control did not significantly reduce any microvascular outcomes (except new or worsening microalbuminuria: RR 0.90, 99% CI 0.85 to 0.96, p<0.001). The authors of the BMJ meta-analysis suggest that intensive blood glucose lowering ‘should be considered with caution and therapeutic escalation should be limited’.
So what?
As we discussed in MeReC Bulletin 2011;21:5 – Improving outcomes in type 2 diabetes, blood glucose control is important and there are no arguments in favour of poor blood glucose control in type 2 diabetes. However, it is likely that a holistic approach to an individual patient’s care, deploying maximal lifestyle interventions (stopping smoking, losing weight, taking more exercise), controlling blood pressure, taking a statin, and taking metformin, seems likely to prevent more complications than a narrower focus on attempting to achieve intensive (rather than good) blood glucose control. This Cochrane review (and the BMJ meta-analysis) considered only the role of blood glucose control in type 2 diabetes, and not any of the other important aspects of care.
Despite the addition of these two new meta-analyses, the evidence overall on intensive compared with conventional blood glucose control has not changed and remains uncertain. There were significant differences between many of the studies included in the meta-analyses — i.e. large ranges for duration of type 2 diabetes, duration of the interventions, age, different groups according to risk of CV disease, and different assessments of blood glucose control.
Overall, as discussed earlier, there appears to be no significant reduction in all-cause mortality, CV mortality, or stroke with intensive blood glucose control conmpared with conventional, but a possible reduction in non-fatal MI. The inconsistencies between the results of the two meta-analyses mainly relate to microvascular outcomes. There seems to be a reduction in certain microvascular events (although studies are inconsistent and some of these endpoints are disease-oriented outcomes e.g. microalbuminuria). These possible benefits also need to be balanced against the significantly increased risk of severe hypoglycaemia with intensive blood glucose control.
This meta-analysis was conducted in a diverse population of patients with type 2 diabetes. There are some data from the 10-year follow up of UKPDS and the CONTROL meta-analysis that more intensive blood glucose control may be more beneficial in younger patients with earlier disease. However, the recent ADDITION-Europe RCT found no significant benefits in CV outcomes for early detection and intensive multifactorial management of type 2 diabetes. The Cochrane review was unable to use individual patient data to assess whether certain characteristics (such as duration of diabetes, history of CV events) affected the results.
The management of type 2 diabetes is complex and there are many issues to consider when prioritising the needs of an individual patient. The authors of both studies suggest a cautious approach when reducing blood glucose in type 2 diabetes. NICE recommends an individualised approach and states that any reduction in HbA1c towards the agreed blood glucose target level is advantageous to future health, but pursuing highly intensive management to HbA1c levels below 6.5% (48mmol/mol) should be avoided. See the recent MeReC Bulletin and the NPC e-learning event on type 2 diabetes which discuss how to best manage blood glucose in the overall context of preventing both macrovascular and microvascular diabetic complications, and the NICE clinical guideline on type 2 diabetes for more information.
Design
Systematic review and meta-analysis of 20 RCTs.
Patients
29,986 adults >18 years with type 2 diabetes (mean age 62 years).
Intervention and comparison
Targeted intensive glycaemic control (n=16,106) vs. targeted conventional glycaemic control (n=13,880), irrespective of which glucose-lowering interventions were used.
Outcomes
Primary outcomes:
- All-cause mortality
- CV mortality (death from MI, stroke and peripheral vascular disease).
Secondary outcomes:
- Macrovascular complications (non-fatal MI, non-fatal ischaemic or haemorrhagic stroke, amputation of lower extremity, and cardiac or peripheral revascularisation
- Microvascular complications (manifestation and progression of nephropathy, end-stage renal disease, manifestation and progression of retinopathy, and retinal photocoagulation)
- Adverse events
- Congestive heart failure
- Hypoglycaemia — definitions may be heterogeneous between trials Hypoglycemia was defined as mild (controlled by patient), moderate (daily activities interrupted but self-managed), or severe (requiring assistance)
- Health-related quality of life measured with validated instruments
- Cost(s) of treatment.
Results
| Outcome | Comparative risks* (95% CI) | RR(95% CI) | No. of participants | Median follow-up | |
| Conventional control | Intensive control | ||||
| All-cause mortality | 88 per 1000 | 89 per 1000 | 1.01 (0.90 to 1.13) p=0.92 |
29,731 | 23.1 months |
| CV mortality | 45 per 1,000 | 48 per 1000 | 1.06 (0.90 to 1.26) p=0.46 |
29,731 | 23.1 months |
| Non-fatal MI | 48 per 1,000 | 42 per 1000 | 0.87 (0.76 to 1.00) p=0.054 |
29,174 | 51 months |
| Non-fatal stroke | 29 per 1,000 | 28 per 1000 | 0.96 (0.80 to 1.16) p=0.68 |
28,760 | 3.5 years |
| Amputation of lower extremity | 20 per 1,000 | 13 per 1000 | 0.64 (0.43 to 0.95) p=0.026 |
6960 | 7.8 years |
| End-stage renal disease | 16 per 1,000 | 14 per 1000 | 0.87 (0.71 to 1.06) p=0.15 |
28,075 | 10.0 years |
| Severe hypoglycaemia | 30 per 1,000 | 61 per 1000 | 2.05 (1.39 to 3.02) p=0.00031 |
28,127 | 2.9 years |
* The conventional control risk is the median control group risk across studies. The intensive control risk = the conventional control risk x the relative effect (RR) of the intervention (and its 95% CI).
Sponsorship Study conducted by Cochrane authors. Most included trials received funding from a private health insurance company or the medical industry to conduct the trial.
Further information can be found on NHS Evidence, in MeReC Bulletin 2011;21(5) – Improving outcomes in type 2 diabetes and in the NPC e-learning materials on type 2 diabetes.
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