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Canadian Stroke Network. The quality of stroke care in Canada. 2011. http://www.canadianstrokenetwork.ca/index.php/quality-stroke-care/ (accessed July 23, 2014). Walter S, Kostopoulos P, Haass A, et al. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. Lancet Neurol 2012; 11: 397–404. Meretoja A, Strbian D, Mustanoja S, Tatlisumak T, Lindsberg PJ, Kaste M. Reducing in-hospital delay to 20 minutes in stroke thrombolysis. Neurology 2012; 79: 306–13. Bray BD, Campbell J, Cloud GC, et al. Bigger, faster? Associations between hospital thrombolysis volume and speed of thrombolysis administration in acute ischemic stroke. Stroke 2013; 44: 3129–35. Barber PA, Hill MD, Eliasziw M, et al. Imaging of the brain in acute ischaemic stroke: comparison of computed tomography and magnetic resonance diffusion-weighted imaging. J Neurol Neurosurg Psychiatry 2005; 76: 1528–33.

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Barber PA, Demchuk AM, Zhang J, Buchan AM, for the ASPECTS Study Group. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Lancet 2000; 355: 1670–74. Demchuk AM, Morgenstern LB, Krieger DW, et al. Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke. Stroke 1999; 30: 34–39. Poppe AY, Hill MD. Hyperglycemia in thrombolysed acute ischemic stroke patients. Int J Stroke 2011; 6: 278. Kent DM, Price LL, Ringleb P, Hill MD, Selker HP. Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke: a pooled analysis of randomized clinical trials. Stroke 2005; 36: 62–65.

Glycaemic control, cardiovascular disease, and mortality in type 2 diabetes Published Online August 1, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60884-9

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Intensive glucose treatment in patients with type 2 diabetes is associated with a reduction in microvascular complications, but the effects on cardiovascular disease remain controversial.1–3 In the ACCORD trial,2 done in 10 251 patients with a mean age of 62·2 years at baseline and type 2 diabetes for at least 10 years, intensive glycaemic treatment was associated with an increased risk of cardiovascular and all-cause mortality. Post-hoc analyses showed that the increased risk occurred in patients who did not achieve concentrations of glycated haemoglobin A1C (HbA1c) lower than 53 mmol/mol (7·0%),4 that the prevalence of neuropathy of the autonomic nervous system was

Molecular model of glycated haemoglobin A1C

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similar in both groups,5 and that only 9·5% and 10·5% of deaths could be attributed to severe hypoglycaemia in the intensive and standard glycaemic therapy groups, respectively.6 Thus, severe hypoglycaemia does not explain the increased mortality and, therefore, this finding could have been due to chance.7 In The Lancet, Hertzel Gerstein and colleagues8 report a further post-hoc analysis of the ACCORD data that was done to investigate the effects of intensive glucose lowering (target HbA1C concentration less than 42 mmol/mol [6·0%]) versus standard glucose lowering (target HbA1C concentration 53–63 mmol/mol [7·0–7·9%]) with multiple antidiabetic drugs on composite outcomes of ischaemic heart disease. Intensive treatment, which patients received for a mean of 3·7 years followed by standard therapy for a further mean 1·2 years, was associated with reductions in non-fatal myocardial infarction (hazard ratio [HR] 0·81, 95% CI 0·70–0·95), revascularisation (0·84, 0·75–0·94), and unstable angina (0·81, 0·67–0·97), and a non-significant reduction in new-onset angina (0·76, 0·55–1·06). In patients who received intensive therapy followed by standard therapy there was a non-significant increase in fatal myocardial infarction (1·68, 0·87–3·24). Adjustment for HbA1C concentration before the transition from intensive to standard treatment attenuated all hazard ratios to neutral, except for that for fatal myocardial infarction (1·87, 0·82–4·26), which favoured standard therapy, although not significantly. Four major trials have tested the effects of intensive versus standard glycaemic control on major cardiovascular www.thelancet.com Vol 384 November 29, 2014

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events in patients with type 2 diabetes: UKPDS (n=3967),1 ADVANCE (n=11 140),2 VADT (n=1791),3 and ACCORD.9 Compared with the other three studies, patients in UKPDS were younger (mean 54 years), had newly diagnosed type 2 diabetes, final HbA1C concentration was higher in the intensive group, and follow-up was longer (mean 10 years). The 10-year follow-up suggested a decreased risk of myocardial infarction and all-cause mortality with early intensive therapy.10 Of the other trials, ACCORD was the only one where intensive treatment was associated with increased cardiovascular mortality, despite the study populations in ADVANCE and VADT being similar (respectively, age 66 and 60 years, duration of diabetes 8 and 11 years, high risk of cardiovascular disease, and achieved HbA1C concentrations of 48 and 52 mmol/mol [6·5% and 6·9%]).3,9 In a meta-analysis of these four trials, intensive glucoselowering treatment was associated with a significant 9% reduction in major cardiovascular events but had no effect on mortality.11 Analysis of prespecified subgroups showed that age younger than 65 years, diabetes duration of less than 5 years, HbA1C concentration lower than 69 mmol/mol (8·5%), and no history of vascular complications were associated with the best cardiovascular outcomes after intensive therapy.11 The results of that meta-analysis should be interpreted in light of the previous Steno-2 study12 (n=160 patients with a mean age of 55 years), in which intensive multifactorial treatment of hyperglycaemia (target HbA1C concentration 48 mmol/mol [6·5%]) and other diabetes risk factors was associated with reduced cardiovascular mortality over 13·3 years (HR 0·43, 95% CI 0·19–0·94). The findings together suggest that early intensive glucose lowering (target HbA1C concentration lower than 53 mmol/mol [7·0%]) in patients with diabetes combined with intensive treatment of other risk factors is likely to result in long-term reductions in cardiovascular disease.13 Thus, the latest post-hoc analysis of the ACCORD data is reassuring, as intensive therapy was associated with significant reductions in the 5-year incidence of ischaemic heart disease (13%), any myocardial infarction (16%), non-fatal myocardial infarction (19%), coronary revascularisation (16%), and unstable angina (19%).8 These potential benefits, however, do not totally negate the potential harmful effect of intensive glycaemic treatment on cardiovascular mortality in selected patients under specific conditions. www.thelancet.com Vol 384 November 29, 2014

Most patients (77·3%) in the ACCORD trial who received intensive glucose-lowering treatment were taking insulin.2 The combination of hyperinsulinaemia and hyperglycaemia has been suggested to induce myocardium steatosis and increased ectopic epicardial adipose tissue that is potentially involved in the development of cardiomyopathy and coronary artery disease.14–16 Further assessment of the risks and benefits is required. In the meantime, it is probably wise to aim for a target HbA1C concentration of less than 64 mmol/mol (8·0%) in patients older than 65 years with comorbidities. *Jean-Louis Chiasson, Jacques Le Lorier Department of Medicine, Université de Montréal, CRCHUM 900 St-Denis Street, Pavillion R, Montréal, QC H2X 0A9, Canada [email protected] We declare no competing interests. 1

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UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545–59. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560–72. Riddle MC, Ambrosius WT, Brillon DJ, et al. Epidemiologic relationships between A1C and all-cause mortality during a median 3·4-year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010; 33: 983–90. Pop-Busui R, Evans GW, Gerstein HC, et al. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care 2010; 33: 1578–84. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 2010; 340: b4909. Lachin JM. Point: intensive glycemic control and mortality in ACCORD—a chance finding? Diabetes Care 2010; 33: 2719–21. Gerstein HC, Miller ME, Ismail-Beigi F, et al, for the ACCORD Study Group. Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial. Lancet 2014; published online Aug 1. http://dx.doi.org/10.1016/S0140-6736(14)60611-5. 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: 129–39. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577–89. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009; 52: 2288–98. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580–91. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care 2014; 37 (suppl 1): S14–80. Winhofer Y, Krssak M, Jankovic D, et al. Short-term hyperinsulinemia and hyperglycemia increase myocardial lipid content in normal subjects. Diabetes 2012; 61: 1210–16. Jankovic D, Winhofer Y, Promintzer-Schifferl M, et al. Effects of insulin therapy on myocardial lipid content and cardiac geometry in patients with type-2 diabetes mellitus. PLoS One 2012; 7: e50077. Gaborit B, Abdesselam I, Dutour A. Epicardial fat: more than just an “epi” phenomenon? Horm Metab Res 2013; 45: 991–1001.

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Glycaemic control, cardiovascular disease, and mortality in type 2 diabetes.

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