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Hyperglycaemia and coronary heart disease: the meta picture - EDITORIAL
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"A glycosylated haemoglobin of 7% for most patients seems reasonable and safe. This goal can be adjusted for individuals in whom the risk associated with hypoglycaemia is deemed low (eg, younger patients with no coronary heart disease) and those in whom the risk would be high (elderly patients with established coronary heart disease)." "Because none of these trials individually reported a significant reduction in primary endpoints for coronary heart disease, a reasonable question is whether the results of this meta-analysis are important and, more broadly, why is there continuing interest in the importance of hyperglycaemia for accelerating coronary heart disease in patients with diabetes?"...."Ray and colleagues' meta-analysis1 underlines the need for additional clinical trial data about the effect of controlling blood sugar on coronary heart disease risk in type 2 diabetes. Intensive glucose-control efforts might need to be started sooner after onset of diabetes, and extended follow-up could be required. The benefit of glucose control on coronary heart disease in type 2 diabetes will certainly not be as great as that produced by blood pressure control or statin treatment. However, on the basis of current information, and the urgent need to address residual risk of coronary heart disease in a rapidly expanding population with type 2 diabetes, it is premature to conclude that glucose control has no part to play."
The Lancet, Volume 373, Issue 9677, Pages 1737 - 1738, 23 May 2009
Theodore Mazzone a
a Department of Medicine, University of Illinois at Chicago, Chicago, IL 61612, USA
In The Lancet today, Kausik Ray and colleagues1 report on the results of a meta-analysis of five carefully executed trials that examined the effect of glucose control on coronary heart disease in patients with type 2 diabetes.2-7 They report significant 17% and 15% reductions in events of non-fatal myocardial infarction and coronary heart disease, respectively, with better control of blood sugar. Because none of these trials individually reported a significant reduction in primary endpoints for coronary heart disease, a reasonable question is whether the results of this meta-analysis are important and, more broadly, why is there continuing interest in the importance of hyperglycaemia for accelerating coronary heart disease in patients with diabetes?
The prevalence of diabetes continues to increase worldwide-currently, 225 million people are affected. The major cause of morbidity and mortality in these patients will be coronary heart disease. Although blood pressure control and statin treatment substantially reduce coronary heart disease events and overall mortality in type 2 diabetes, residual risk remains for coronary heart disease.8 Observational data clearly relate indices of glycaemic control to coronary heart disease events in large populations. A wealth of mechanistic and pathophysiological information establishes the negative effects of hyperglycaemia, both direct and indirect (figure), on vessel wall homoeostasis.9 Although we currently lack consistent data in animal models to link hyperglycaemia with accelerated atherosclerosis (because of the confounding effect of worsened hyperlipidaemia produced by hyperglycaemia in these models), we have data in patients with type 1 diabetes that represent an excellent test of the relation between hyperglycaemia and coronary heart disease. The report from the DCCT/EDIC Study Research Group showed that, with extended follow-up, tight glycaemic control significantly reduced coronary heart disease (by 57%) in patients with type 1 diabetes.10 This result reasonably establishes the proof of concept that control of hyperglycaemia has a beneficial effect on risk of coronary heart disease. The remaining important questions to be addressed in type 2 diabetes are: what proportion of residual risk of coronary heart disease can be ascribed to hyperglycaemia; what will be the effect of controlling hyperglycaemia with currently available therapies on residual risk; and what are the potential negative effects of currently available therapies?
Why have individual trials failed to show a beneficial effect of glucose control on coronary heart disease? All randomised clinical trials (of necessity) include design details (specific populations, therapeutic interventions and targets, endpoints, treatment and observation periods) that importantly influence interpretation of results. As pointed out by Ray and colleagues for the trials in their analysis, negative results could have been produced if event rates were lower than expected, differences in glycaemic control were not large enough to achieve maximum clinical benefit, or if duration of the intervention (or observation) was shorter than optimum. The result of any clinical trial must always be interpreted with its specific design in mind, and in the bigger context of the results of related clinical trials and important pathophysiological relations.
In this bigger picture, what would be a reasonable approach for the clinician attempting to optimally manage risk of coronary heart disease in type 2 diabetes? In view of Ray and colleagues' meta-analysis,1 the results in patients with type 1 diabetes,10 and a wealth of pathophysiological information,9 it is important that clinicians should not discount the potential benefits of managing hyperglycaemia. This position becomes even stronger when one considers the salutary effects of managing hyperglycaemia on microvascular disease (and the negative effects of microvascular disease on coronary heart disease; figure), and the results from UKPDS showing that better glucose control resulted in reduced coronary heart disease in type 2 diabetes during extended follow-up.11 A glycosylated haemoglobin of 7% for most patients seems reasonable and safe. This goal can be adjusted for individuals in whom the risk associated with hypoglycaemia is deemed low (eg, younger patients with no coronary heart disease) and those in whom the risk would be high (elderly patients with established coronary heart disease).
Ray and colleagues' meta-analysis1 underlines the need for additional clinical trial data about the effect of controlling blood sugar on coronary heart disease risk in type 2 diabetes. Intensive glucose-control efforts might need to be started sooner after onset of diabetes, and extended follow-up could be required. The benefit of glucose control on coronary heart disease in type 2 diabetes will certainly not be as great as that produced by blood pressure control or statin treatment. However, on the basis of current information, and the urgent need to address residual risk of coronary heart disease in a rapidly expanding population with type 2 diabetes, it is premature to conclude that glucose control has no part to play.
I thank Stephanie Thompson for assistance with manuscript preparation, and Zhi Hua Huang for assistance with graphics. I declare that I have no conflicts of interest.
References
1 Ray KK, Kondapally Seshasai SR, 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: 1765-1772.
2 UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854-865.
3 UK Prospective Diabetes Study (UKPDS) 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: 837-853.
4 Duckworth W, Abraira C, Moritz T, et alfor the VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129-139.
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: 2545-2559.
6 Dormandy JA, Charbonnel B, Eckland DJ, et alon behalf of the 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: 1279-1289.
7 The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-2572.
8 Mazzone T. Prevention of macrovascular disease in patients with diabetes mellitus: opportunities for intervention. Am J Med 2007; 120 (suppl): S26-S32.
9 Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 2008; 371: 1800-1809.
10 The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643-2653.
11 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: 1577-1589.
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