Glycosylated haemoglobin (HbA1c) and cardiovascular (macrovascular) disease (CVD)

• in persons with diabetes, chronic hyperglycaemia (assessed by glycosylated haemoglobin level) is related to the development of microvascular disease (1). However, the relation of glycosylated hemoglobin to macrovascular disease is less well-defined
• intensive blood glucose control in patients with type 2 diabetes
  • large retrospective cohort study supports findings from RCTs that intensive blood glucose control in patients with type 2 diabetes may increase the risk of harm. This study found an association between increased all-cause mortality above and below an HbA1c level of about 7.5% (59mmol/mol) (2)
    • results showed a general U-shaped association, with the lowest hazard ratio (HR) at an HbA1c of about 7·5%. HR for all-cause mortality in people given insulin-based regimens (2834 deaths) versus those given combination oral agents (2035) was 1·49 (95% CI 1·39-1·59)
      • intensifying treatment with insulin was associated with a greater risk of these events than intensifying treatment with oral hypoglycaemic agents
        
  • a meta-analysis of randomised controlled trials (RCTs) (3) suggests a small benefit of intensive glucose control in people with type 2 diabetes in reducing coronary heart disease (CHD), but not stroke or death. However, the benefit is not as great as that achieved by blood pressure (BP) control or lipid lowering
    • a meta-analysis of five RCTs (total n=33,040) and found that intensive therapy statistically significantly reduced non-fatal MI (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.75 to 0.93) and CHD (fatal and non-fatal MI; OR 0.85, 95%CI 0.77 to 0.93), compared with standard treatment
      • number needed to treat (NNT) over five years was estimated as 87 and 69, respectively
      • no statistically significant differences between treatment groups with regard to stroke (OR 0.93, 95%CI 0.81 to 1.06) or all-cause mortality (OR 1.02, 95%CI 0.87 to 1.19)
      • intensive glucose control was associated with an increased incidence of hypoglycaemic episodes (38.1% vs. 28.6%) and severe hypoglycaemic events (2.3% vs. 1.2%)
      • mean reduction in HbA1c was 0.9% (approximately 10 mmol/mol) lower with intensive treatment rather than standard treatment
      • a review states that "...remains uncertain whether intensive glucose control (e.g. the addition of hypoglycaemic drugs to reduce HbA1c to levels significantly below that often achieved in clinical practice) offers any significant benefit beyond that achievable by implementing other interventions to reduce cardiovascular (CV) risk (i.e. smoking cessation, exercise, losing weight, controlling BP, lowering cholesterol, taking metformin)..." (4)
        
        
• ACCORD (5) and ADVANCE (6) were set up to assess whether intensive glucose control strategies offered any advantage over standard therapies with regard to major CV events
  • the ACCORD study, intensive treatment was stopped early because recipients showed significantly higher all-cause mortality than those on standard therapy (5.0% vs. 4.0%, P=0.04)
    • primary endpoint (a composite of myocardial infarction, stroke, and CV death) did not differ significantly between the groups
      • In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%)
      • finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up
    • in the ADVANCE study, intensive therapy showed no significant effect on macrovascular events or all-cause mortality, although it did reduce nephropathy
• VADT (7)
  • an open-label RCT of 1,791 US military veterans (mean age 60 years) with poorly-controlled type 2 diabetes randomised to intensive or standard glucose control
    • over a median of 5.6 years, intensive treatment (median HbA1c 6.9%) with oral hypoglycaemic drugs plus insulin, if necessary, was not associated with a statistically significant reduction in major CV events (a composite of MI, stroke, death from CV causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, or amputation for ischaemic gangrene) compared with less intensive, standard treatment (median HbA1c 8.4%)
    • patients in the intensive-treatment arm were more likely to suffer hypoglycaemic episodes, including impaired consciousness (9 vs. 3 per 100 patient-years, P<0.001) or complete loss of consciousness (3 vs. 1 per 100 patient-years, P<0.001)
      
      
• intensive glucose control in the intensive care unit (ICU) setting
  • intensive glucose control increased mortality among adults in the ICU (8)
    • a blood glucose target of < = 10mmol/l (180 mg or less per deciliter) resulted in lower mortality than did a target of 4.5 to 6.0 mmol per liter (81 to 108 mg per deciliter)

Notes:

• a follow-up study based on the DCCT population has provided evidence that intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes (9)

Reference:

• (1) Lancet. 1998 Sep 12;352(9131):837-53
• (2) Currie CJ, et al. Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study. Lancet 2010;375:481-9
• (3) Ray KK, 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;373:1765-72
• (4) MeReC Monthly No.17 August 2009.
• (5) The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59
• (6) The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72
• (7) Duckworth W, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360
• (8) NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients.N Engl J Med. 2009 Mar 26;360(13):1283-97
• (9) Nathan DM et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005 Dec 22;353(25):2643-5