This site is intended for healthcare professionals only

Hyperglycaemia and coronary heart disease: The meta picture

Jiten Vora

The major cause of morbidity and mortality in people with type 2 diabetes continues to be cardiovascular (CV) disease and, in particular, coronary heart disease (CHD). Recent improvements in blood pressure control and cholesterol lowering have substantially reduced CHD events and overall mortality in type 2 diabetes, as exemplified by event rates observed in recent large-scale trials. However, residual risk in CHD does continue (Mazzone, 2007; Mazzone et al, 2008).

Epidemiological data clearly demonstrate that measures of glycaemic control are related to coronary artery disease events in individuals with type 2 diabetes (UK Prospective Diabetes Study [UKPDS] Group, 1998a; 1998b). In addition, there are numerous in vivo and in vitro studies examining surrogate endpoints, demonstrating the pathophysiological negative effects of hyperglycaemia on the development of atherosclerosis, including endothelial dysfunction, local inflammatory response, oxidative stress, altered matrix composition, altered lipoprotein composition and concentration, and the presence of accelerative factors, such as abnormal renal function.

Furthermore, in type 1 diabetes, long-term follow-up of the DCCT/EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) study has revealed long-term beneficial effects on CHD, with a 57% reduction during the extended follow-up period of the study (Duckworth et al, 2009). Similarly, extended follow-up of those who have had type 2 diabetes for up to 10 years has demonstrated a “memory” effect of improved glycaemic control, resulting in a reduction in CHD events during a period when no significant changes were noted between the intensively and conventionally treated group. Clearly, improved glycaemic control has long-term benefits on CV events.

Why is it that large, well controlled trials have failed to demonstrate a beneficial effect of improved glycaemic control on CV events (Dormandy et al, 2005; ACCORD [Action to Control Cardiovascular Risk in Diabetes] Study Group, 2008; ADVANCE [Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation] Collaborative Group, 2008; Duckworth et al, 2009)? While many of these trials provide details of the populations enrolled, therapeutic interventions used to specific targets, endpoints evaluated and observation periods, the lower than expected event rates would, by the nature of these studies, be responsible for negative results. Also, the differences in glycaemic control, albeit statistically significant, were not large enough to demonstrate clinical benefit during the observation period.

A meta-analysis of these studies examining the effect of glucose control on CHD has, however, revealed a significant reduction of 17% and 15% in events of non-fatal myocardial infarction and CHD, respectively, due to improved glycaemic control (Ray et al, 2009). Indeed, intensive glycaemic control compared with conventional glycaemic control significantly reduced coronary events in the meta-analysis without an increased risk of death. The authors of the meta-analysis were clear, however, in recognising the limitations of this report in that the mechanism, speed and extent of HbA1c reduction may have had different effects in different populations. It is also clear that the meta-analysis did not demonstrate a significant impact of improved glycaemia on overall mortality.

In view of the recent meta-analysis (Ray et al, 2009), which provides appropriate information given the lower than expected event rates in the individual trials and the results available in the long-term studies of type 1 diabetes, together with the enormous database on the pathophysiology of atherosclerosis in the presence of hyperglycaemia, it would appear prudent to strive for improved glycaemic control. This is particularly the case, as the impact on macrovascular disease would of course be in parallel to the enormous benefit in microvascular disease. While HbA1c goals need to be individualised, it would appear that a value of somewhere around 7% (53 mmol/mol) for most people with type 2 diabetes would be appropriate, so long as hypoglycaemia is avoided.

With the legacy effect examined in the UKPDS (Holman et al, 2008), intensive glucose control efforts might need to be initiated sooner after the onset of diabetes. Perhaps other studies would also be initiated to examine the value of improved glycaemic control to the levels currently being discussed, but such that the improvement is initiated as soon after the diagnosis of diabetes as possible as opposed to many of the recent studies that have, by nature of their inclusion criteria, examined people who have a duration of diabetes of approximately 10 years or so. Most importantly, it would be cavalier to ignore the effects of glycaemia on CV disease, though the effects may be smaller than those witnessed with blood pressure and lipid control.

The major cause of morbidity and mortality in people with type 2 diabetes continues to be cardiovascular (CV) disease and, in particular, coronary heart disease (CHD). Recent improvements in blood pressure control and cholesterol lowering have substantially reduced CHD events and overall mortality in type 2 diabetes, as exemplified by event rates observed in recent large-scale trials. However, residual risk in CHD does continue (Mazzone, 2007; Mazzone et al, 2008).

Epidemiological data clearly demonstrate that measures of glycaemic control are related to coronary artery disease events in individuals with type 2 diabetes (UK Prospective Diabetes Study [UKPDS] Group, 1998a; 1998b). In addition, there are numerous in vivo and in vitro studies examining surrogate endpoints, demonstrating the pathophysiological negative effects of hyperglycaemia on the development of atherosclerosis, including endothelial dysfunction, local inflammatory response, oxidative stress, altered matrix composition, altered lipoprotein composition and concentration, and the presence of accelerative factors, such as abnormal renal function.

Furthermore, in type 1 diabetes, long-term follow-up of the DCCT/EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) study has revealed long-term beneficial effects on CHD, with a 57% reduction during the extended follow-up period of the study (Duckworth et al, 2009). Similarly, extended follow-up of those who have had type 2 diabetes for up to 10 years has demonstrated a “memory” effect of improved glycaemic control, resulting in a reduction in CHD events during a period when no significant changes were noted between the intensively and conventionally treated group. Clearly, improved glycaemic control has long-term benefits on CV events.

Why is it that large, well controlled trials have failed to demonstrate a beneficial effect of improved glycaemic control on CV events (Dormandy et al, 2005; ACCORD [Action to Control Cardiovascular Risk in Diabetes] Study Group, 2008; ADVANCE [Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation] Collaborative Group, 2008; Duckworth et al, 2009)? While many of these trials provide details of the populations enrolled, therapeutic interventions used to specific targets, endpoints evaluated and observation periods, the lower than expected event rates would, by the nature of these studies, be responsible for negative results. Also, the differences in glycaemic control, albeit statistically significant, were not large enough to demonstrate clinical benefit during the observation period.

A meta-analysis of these studies examining the effect of glucose control on CHD has, however, revealed a significant reduction of 17% and 15% in events of non-fatal myocardial infarction and CHD, respectively, due to improved glycaemic control (Ray et al, 2009). Indeed, intensive glycaemic control compared with conventional glycaemic control significantly reduced coronary events in the meta-analysis without an increased risk of death. The authors of the meta-analysis were clear, however, in recognising the limitations of this report in that the mechanism, speed and extent of HbA1c reduction may have had different effects in different populations. It is also clear that the meta-analysis did not demonstrate a significant impact of improved glycaemia on overall mortality.

In view of the recent meta-analysis (Ray et al, 2009), which provides appropriate information given the lower than expected event rates in the individual trials and the results available in the long-term studies of type 1 diabetes, together with the enormous database on the pathophysiology of atherosclerosis in the presence of hyperglycaemia, it would appear prudent to strive for improved glycaemic control. This is particularly the case, as the impact on macrovascular disease would of course be in parallel to the enormous benefit in microvascular disease. While HbA1c goals need to be individualised, it would appear that a value of somewhere around 7% (53 mmol/mol) for most people with type 2 diabetes would be appropriate, so long as hypoglycaemia is avoided.

With the legacy effect examined in the UKPDS (Holman et al, 2008), intensive glucose control efforts might need to be initiated sooner after the onset of diabetes. Perhaps other studies would also be initiated to examine the value of improved glycaemic control to the levels currently being discussed, but such that the improvement is initiated as soon after the diagnosis of diabetes as possible as opposed to many of the recent studies that have, by nature of their inclusion criteria, examined people who have a duration of diabetes of approximately 10 years or so. Most importantly, it would be cavalier to ignore the effects of glycaemia on CV disease, though the effects may be smaller than those witnessed with blood pressure and lipid control.

REFERENCES:

Action to Control Cardiovascular Risk in Diabetes Study Group (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358: 2545–59
ADVANCE Collaborative Group (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358: 2560–72
Dormandy JA, Charbonnel B, Eckland DJ et al (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective piogliAzone Clinical Trial in macroVascular Events): a randomised controlled trial. Lancet 366: 1279–89 
Duckworth W, Abraira C, Moritz T et al (2009) Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med 360: 129–39
Holman RR, Paul SK, Bethel MA et al (2008) 10-year follow-up of intensive glucose control 
in type 2 diabetes (UKPDS 80). N Engl J Med 359: 1577–89
Mazzone T (2007) Prevention of macrovascular disease in patients with diabetes mellitus: opportunities for intervention.Am J Med 120: S26–32
MazzoneT, Chait A, Pluzky J (2008) Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 371: 1800–09
Ray KK, Seshasai SR, Wijesuriya S et al (2009) Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 373: 1765–72
UK Prospective Diabetes Study (UKPDS) Group (1998a) Effect of intensive blood glucose control with Metformin on complications in overweight patients with type 2 diabetes (UKPDS 24). Lancet 352: 854–65
UK Prospective Diabetes Study (UKPDS) Group (1998b) 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 352: 837–53

;
Free for all UK & Ireland healthcare professionals

Sign up to all DiabetesontheNet journals

 

By clicking ‘Subscribe’, you are agreeing that DiabetesontheNet.com are able to email you periodic newsletters. You may unsubscribe from these at any time. Your info is safe with us and we will never sell or trade your details. For information please review our Privacy Policy.

DiabetesontheNet Logo

Are you a healthcare professional? This website is for healthcare professionals only. To continue, please confirm that you are a healthcare professional below.

We use cookies responsibly to ensure that we give you the best experience on our website. If you continue without changing your browser settings, we’ll assume that you are happy to receive all cookies on this website. Read about how we use cookies.