Dr Alan Begg reviews trial evidence on the clinical outcomes of tight glucose control in patients with type 2 diabetes

There is currently much debate on the ideal level of glycated haemoglobin (HbA1c) that should be achieved in people with diabetes, and the overall benefit of tight glycaemic control on cardiovascular outcomes.

Three of the current quality and outcomes framework (QOF) clinical indicators for diabetes—DM 23, DM 24, and DM 25—relate to graded achievement levels of HbA1c, which range from ?7, ?8, and ?9, respectively.1 This range of achievement levels is designed to provide an incentive to improve glycaemic control across a distribution of differing HbA1c levels. The aim of the QOF in lowering HbA1c levels is based on an assumption of a linear level of cardiovascular risk with hyperglycaemia and that better glycaemic control will lead to reduced cardiac risk. Do we, however, have the evidence to fully support this?

UKPDS—risk reductions in death

A 10-year follow up of patients in two components of the United Kingdom Prospective Diabetes Study (UKPDS 33 and 34) has suggested that there may be a long-term benefit from tight glycaemic control in the early years after diagnosis of diabetes. Risk reductions in death from any cause were observed (p=0.007 in the sulfonylurea-insulin group and p=0.002 in the metformin group) despite an early loss of glycaemic differences in intensively and conventionally treated groups during non-randomised follow up.2

ACCORD—adverse effects of tight control

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,3 10,251 patients with a median HbA1c level of 8.1% were assigned to receive intensive therapy (target <6%) or standard therapy (target of 7.0%–7.9%). Within 4 months of randomisation, the median HbA1c level had fallen from 8.1% to 6.7% in the intensive therapy group and to 7.5% in the standard therapy group.

The trial was stopped early after a 3.5 year mean follow up as a result of a higher mortality rate in the intensive therapy group. During follow up, 257 patients in the intensive therapy group died compared with 203 patients in the standard therapy group (hazard ratio [HR] 1.22; 95% confidence interval [CI] 1.01 to 1.46, p=0.04). This increase in mortality was not accompanied by any significant benefit in a reduction of major cardiovascular events; in addition, weight gain of over 10 kg (27.8% vs 14.1%) and hypoglycaemia also occurred more frequently in the intensively treated group. The percentage of individuals requiring assistance for hypoglycaemia was 16.2% in the intensive group, compared with 5.1% for those on standard therapy.3

ADVANCE—benefits of tight control

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial was published at the same time as the ACCORD study, but reported a different outcome of intensive glucose control on vascular outcomes.4 This trial involved 11,140 patients with type 2 diabetes. Individuals were assigned to either standard glucose control or intensive glucose control, defined as the use of modified-release gliclazide plus other drugs to achieve a HbA1c level of ?6.5%. After a median follow-up period of 5 years, the mean HbA1c level was 6.5% in the intensive control group compared with 7.3% in the standard control group. The intensive control level was not reached until 4 years of treatment. Intensive therapy reduced the incidence of major microvascular events (9.4% vs 10.9%; HR 0.86; 95% CI 0.77 to 0.97, p=0.01) because of a reduction in the incidence of nephropathy (4.1% vs 5.2%; HR 0.79; 95% CI 0.66 to 0.93, p=0.006), with no significant effect on retinopathy (p=0.5). However, severe hypoglycaemia was more common in the intensive control group (2.7% vs 1.5%). The degree of glucose control had no significant effect on macrovascular events, death from cardiovascular causes, or death from any cause.4

The ADVANCE trial had previously shown that a fixed combination of perindopril and indapamide in patients with type 2 diabetes reduced the risk of major microvascular and macrovascular events including death due to a mean systolic blood pressure reduction of 5.6 mmHg (diastolic blood pressure reduction 2.2 mmHg) compared with placebo.5 However, the separate reductions in macrovascular and microvascular events, although similar, were not independently significant (p=0.16).6 When the combined effects of blood pressure lowering and glycaemic control were examined, there were significant beneficial effects for all renal events, new or worsening nephropathy, and new onset micro- and macro-albuminuria.6

In the ADVANCE study there was no significant difference between the two groups in the rate of death from any cause or death from cardiovascular causes. The reasons given for the different outcomes between the ACCORD and ADVANCE trials are:4,7

  • the initial median level of HbA1c (8.1% compared with 7.2%, respectively)
  • the pace of glucose lowering—a period of 4 months in ACCORD, and 4 years in ADVANCE
  • excess weight gain and increased levels of hypoglycaemia in the ACCORD trial.

The data from the ADVANCE trial have been used to define the factors that are significant predictors of cardiovascular risk in people with diabetes: age at diagnosis, duration of diabetes, sex, pulse pressure, treated hypertension, atrial fibrillation, retinopathy, HbA1c, albumin:creatinine ratio, and non-high-density lipoprotein cholesterol level at baseline.8 However, whether a risk engine developed from this data receives universal acceptance remains to be seen.

VADT—reduction in the progression of albuminuria

The Veterans Affairs Diabetes Trial (VADT) investigated the effect of intensive and standard glucose control on cardiovascular outcomes in patients with poorly controlled type 2 diabetes.9 The results did not show any benefits of intensive glucose lowering on major cardiovascular events, death, or microvascular complications, with the exception of the progression of albuminuria (p=0.01).9

PROactive Study

The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) recruited 5238 patients with type 2 diabetes and no evidence of macrovascular disease to receive 15 mg titrated to 45 mg pioglitazone, or placebo.10 The primary endpoint of all-cause mortality, non-fatal MI, acute coronary syndrome, stroke, endovascular or surgical intervention on the coronary or leg arteries, or amputation above the ankle was not significant (HR 0.90; 95% CI 0.80–1.02, p=0.095). This was mainly as a result of reduced cardiac and leg revascularisations. However, the main predefined secondary endpoint of all-cause mortality, MI, or stroke showed significant reduction in the pioglitazone group (HR 0.84; 95% CI 0.72–0.98, p=0.027). The reduction in HbA1c was 0.8 in the pioglitazone group compared with 0.3 in the placebo group (p<0.001) despite an increased use of metformin and insulin in the latter group.10

Meta-analysis of trial data

The results of UKPDS, ACCORD, ADVANCE, and VADT trials, as well as the PROactive study have been combined in a meta-analysis that indicates the effect of intensive glycaemic control as a possible 17% reduction in non-fatal myocardial infarction and a 15% reduction in coronary heart disease events.11 No significant effect was seen on all-cause mortality or stroke. The limitations of this meta-analysis are the significant heterogeneity between the trials included and that none of the trials individually reported a significant reduction in primary end points for coronary heart disease.12,13

National guidance

The NICE guideline on the management of type 2 diabetes recommends that when setting individual targets for HbA1c, which in general will be above 6.5%, the patient himself/herself should be involved in the decision, and that highly intensive management to levels of <6.5% should be avoided.14 Individuals should be encouraged to maintain their own target bearing in mind the risk of possible side-effects of hypoglycaemia and impaired quality of life. This should be achieved through a combination of lifestyle modification and medication on the basis that any progress towards that target will be advantageous to future health.14

The draft SIGN guideline on the management of diabetes, published in September 2009, recommends aiming for a target HbA1c of between 6.5% and 7% in people with diabetes to reduce the risk of microvascular and macrovascular disease. Targets should be set for individuals in order to balance the benefit with any possible harm arising from either hypoglycaemia or weight gain. The wording in the final guideline, due for launch on 23 March 2010, will be a useful guide to primary care teams on how intensively they should lower HbA1c in pursuit of QOF targets.

Conclusion

At present, although we may not have convincing evidence that reducing HbA1c targets below 7% has additional benefit in preventing cardiovascular disease, using the approach in the ADVANCE trial and gradually reaching 6.5% may minimise the effects of nephropathy in patients with diabetes.5 This is important for GPs not only in achieving clinical indicator DM 23, but also DM 13 (record of micro-albuminuria testing), DM 22 (record of estimated glomerular filtration rate or serum creatinine testing), and DM 15 (the percentage of patients with proteinuria or micro-albuminuria who are treated with angiotensin-converting enzyme inhibitors [or angiotensin II receptor blockers]).1

  1. British Medical Association, NHS Employers. Quality and outcomes framework guidance for GMS contract 2009/10. London: BMA, 2009.
  2. Holman R, Paul S, Bethel M et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359 (15): 1577–1589.
  3. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein H, Miller M et al. Intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358 (24): 2545–2559.
  4. ADVANCE Collaborative Group, Patel A, MacMahon S et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358 (24): 2560–2572.
  5. Patel A, ADVANCE Collaborative Group, MacMahon S et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370 (9590): 829–840.
  6. Zoungas S, de Galan B, Ninomiya T et al. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: New results from the ADVANCE trial. Diabetes Care 2009; 32 (11): 2068–2074.
  7. Fisher M. What is the best way of intensively treating patients with type 2 diabetes? J R Coll Physicians Edinb 2009; 39: 327.
  8. ADVANCE trial website. ADVANCE reveals new insights in the fight against severe diabetes complications. www.advance-trial.com/static/html/healthcare/contents.asp?P=37#_ (accessed 7 January 2010).
  9. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360 (2): 129–139.
  10. Dormandy J, Charbonnel B, Eckland D et al; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366 (9493): 1279–1289.
  11. Ray K, Seshasai S, Wijesuriya S et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373 (9677): 1765–1772.
  12. Feher M, Monro N. Controlling hyperglycaemia and cardiovascular benefit. Diabetes and Primary Care 2009; 11 (3): 146.
  13. Mazzone T. Hyperglycaemia and coronary heart disease: the meta picture. Lancet 2009; 373 (9677): 1737–1738.
  14. The National Collaborating Centre for Chronic Conditions. Type 2 diabetes: National clinical guideline for management in primary and secondary care (update). London: Royal College of Physicians, 2008. Available at: www.nice.org.uk/nicemedia/pdf/CG66FullGuideline0509.pdf G

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