8 February 2010
A large retrospective cohort study of patients with type 2 diabetes receiving intensive glucose control treatment suggests that the risk of all-cause mortality increases above and below an HbA1c level of about 7.5% (59mmol/mol). Intensifying treatment with insulin was associated with a greater risk of these events than intensifying treatment with oral hypoglycaemic agents.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
NICE guidance on the management of type 2 diabetes recommends that patients should be involved in setting their individual glycated haemoglobin (HbA1c) target, which may be above the general target of 6.5% (48mmol/mol). NICE recommends adding a second oral drug where patients are unable to reach their agreed target by lifestyle modification or monotherapy with an oral hypoglycaemic agent (usually metformin). Insulin therapy is suggested by NICE as an option where the HbA1c does not fall below 7.5% (59mmol/mol), or does not reach an agreed higher target.
Health professionals may wish to consider the implications of the present study in their discussion with patients about risks and benefits of intensifying drug treatment and setting of individual HbA1c targets, especially if considering an HbA1c target below 7.5%. The study suggests that any benefits of glucose lowering below this level (e.g. a reduction in microvascular events) could be offset by an increased risk of death and cardiovascular events, especially if insulin is used.
What is the background to this?
As the NICE full guideline for diabetes notes, the risk of microvascular and macrovascular complications of type 2 diabetes is strongly associated with increased HbA1c. However, as we have blogged previously, it remains uncertain whether intensive glucose control (the addition of hypoglycaemic drugs to reduce HbA1c to levels significantly below that of standard treatments) in type 2 diabetes offers any significant benefit in addition to that achievable by successful implementation of other interventions to reduce cardiovascular risk (including smoking cessation, exercise, losing weight, controlling blood pressure, taking statins, etc).
The ACCORD, ADVANCE and VADT RCTs did not identify a consistent significant benefit of intensive glycaemic control in the treatment of type 2 diabetes with regard to CV outcomes and mortality. Indeed, the ACCORD study, which compared treatments that aimed to achieve HbA1c levels of less than 6.0% (42mmol/mol) with those of between 7.0% (53mmol/mol) and 7.9% (63mmol/mol) was stopped early because of an increased risk of death in the intensive treatment arm.
The paper discussed in this blog is a retrospective study using data from the UK General Practice Research Database (GPRD) from November 1986 to November 2008 that evaluated the association between all-cause mortality and HbA1c levels in patients with type 2 diabetes. It included about 28,000 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral hypoglycaemic agents, and about 20,000 who had changed regimens to include insulin. All patients were older than 50 years.
What does the study claim?
The study identified that a mean HbA1c level of about 7.5% was associated with the lowest risk of all-cause mortality, and that an increase above or a decrease below this level was associated with a greater risk. This relationship was apparent regardless of whether treatment was intensified with insulin or with oral hypoglycaemic agents. However, with insulin treatment the risk of all-cause mortality was greater. Also the range of HbA1c over which there was no statistically significant difference from 7.5% was narrower (about 7.5% to 8.9% with insulin) than that seen with oral hypoglycaemic therapy (about 6.9% to 9.4%). The authors suggest that diabetes guidelines might need revision to include a minimum HbA1c value.
This study demonstrates a ‘U-shaped’ relationship between HbA1c levels and mortality and cardiovascular events in patients with type 2 diabetes receiving combination blood glucose lowering treatment, with an optimum level of about 7.5%. If these results are true, they suggest that any attempt to reduce HbA1c below this level may not be justified on the basis of reducing death — at least in patients aged over 50, who formed the study population in the present study. NICE guidelines recommend that further intensification of therapy, usually with insulin, should be considered for those patients who are unable to achieve an HbA1c of 7.5% on dual oral hypoglycaemic therapy. Importantly however, NICE also advise that patients should be involved in setting their individual drug target. Health professionals may wish to consider the implications of the present study in their discussion with patients regarding the risks and benefits of further intensifying therapy, especially if an HbA1c level below 7.5% and insulin therapy is being considered.
As we have previously blogged, and as discussed in a recent EBM review, a meta-analysis of RCTs of intensive glucose lowering regimens versus standard control identified only a modest benefit for intensive therapy for some macrovascular outcomes (non-fatal MI and coronary heart disease, NNTs 131 [95%CI 84 to 349] and 91 [95%CI 70 to 155] , respectively, over a mean of 5 years (range 2.9 to 10.1 years), but did not find a significant benefit for stroke, heart failure or mortality. The EBM review considered that the benefits and safety of HBA1c targets below 7.0% is uncertain and may depend on the population and regimen used. Long-term follow up of UKPDS does suggest benefits of intensive glucose control lowering in terms of mortality and all diabetes-related endpoints. However, we should remember that during the intervention phase of UKPDS, the median HbA1c was 7.0% in the intensive control group, whereas at the end of the intervention phase and start of the follow-up, this was 7.9%. In ACCORD and ADVANCE, no significant macrovascular benefits were seen despite HbA1c levels of 6.4% and 6.5%, respectively, being reached.
The present study supports the NICE recommendation not to pursue HbA1c targets below 6.5%. Consistent with the results of the ACCORD study, the study found that intensifying drug treatment to achieve such low levels carries an increased risk of death. However, the study also suggests that it may be unnecessary to intensify treatment to reduce HbA1c levels below 7.5% and gives some reassurance to patients for whom a 7.5% target is inappropriate or unachievable. It failed to find a statistically significant increase in mortality for HbA1c levels up to about 9%.
This study has several limitations, which means that its findings should be interpreted with caution. Observational data such as these are prone to confounding. Unlike in the setting of an RCT, in ‘real life’, treatment plans are chosen, changed, or actively not chosen in the light of individual patients’ risk factors, preferences and tolerability or response to other drugs. Thus observed differences in outcomes may well be due to differences among the patients, not only the different treatments. Observational studies attempt to adjust for these differences by statistical modelling, but this requires certain assumptions and of course can take into account only those factors that have been recognised. This analysis required adjustments for a considerable number of confounding factors, such as gender, smoking status, age, cholesterol level, and presence of left ventricular dysfunction, which all had a significant effect on mortality within the cohort studied. There are also uncertainties about the influences of drugs prescribed for prevention of cardiovascular disease and the reported HbA1c levels. The study did not examine the causes of death, and, therefore, provides no information on the mechanism(s) responsible for the increases in death seen at different HbA1c levels.
An accompanying editorial considers that the most plausible explanation for the findings of this study is hypoglycaemia. However, post-hoc analyses of the ACCORD study found no association of symptomatic hypoglycaemic episodes and mortality, and suggests that many other factors are involved.
Finally, it should be noted that the present study contains no direct information on the relationship between HbA1c and mortality in people managed on monotherapy with oral hypoglycaemic agents, for which NICE recommends an HbA1c target of 6.5% or a higher target agreed with the patient.
Design: Retrospective cohort study.
Patients and interventions: 27,965 patients (50 years or older) identified from the UK GPRD with type two diabetes with treatment intensified from monotherapy to combination therapy with oral hypoglycaemic agents and 20,005 who had changed to regimens that included insulin.
Outcomes: Mortality (primary outcome) and cardiovascular events were assessed as a function of HbA1c level.
Results: Observed mean HbA1c levels were divided into deciles. The study identified that a mean HbA1c level of about 7.5% (decile range 7.4% to 7.7%) was associated with the lowest risk all-cause mortality, and that a level above or below this was associated with a greater risk (e.g. combined cohort: mean HbA1c 6.4% vs. 7.5%, HR 1.52, 95%CI 1.32 to 1.76, P<0.0001; mean HbA1c 10.6% [92mmol/mol] vs 7.5%, HR 1.79, 95%CI 1.56 to 2.06, P<0.0001). This relationship was apparent regardless of whether treatment was intensified with insulin or with oral hypoglycaemic agents. However, with insulin treatment the risk of all-cause mortality was greater (HR 1.49, 95%CI 1.39 to 1.59, P<0.0001) compared with those given combination oral drugs. Also, with insulin treatment the range of HbA1c deciles above and below 7.5% over which there was no significant difference (P>0.05) from the 7.5% decile was narrower (mean HbA1c deciles 7.5% to 8.9%) than that seen with intensive oral hypoglycaemic therapy (mean HbA1c deciles 6.9% to 9.4%).
Analysis of the relationship between cardiovascular events and HbA1c identified the same general U-shaped association as mortality and HbA1c.
Sponsorship: The study was funded by Eli Lilly and Company
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