Prevention of cardiovascular disease through glycemic control in type 2 diabetes: A meta-analysis of randomized clinical trials

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Abstract

Background and aims

Randomized clinical trials (RCTs) aimed at the assessment of the efficacy of lowering blood glucose in the prevention of diabetic complications have always failed to detect a significant effect on cardiovascular events. Aim of this meta-analysis is the assessment of the effects of improvement of glycemic control on the incidence of cardiovascular diseases in patients with type 2 diabetes.

Methods

The RCTs were included in this meta-analysis if: a) the between-group difference in mean HbA1c during the trial was at least 0.5%, b) they had a planned duration of treatment of at least 3 years, c) if they had a cardiovascular endpoint. Data for analysis were extracted independently by two observers and potential contrasts were resolved by a senior investigator.

Results

Five studies (17,267 and 15,362 patients in the intensive and conventional therapy groups, respectively) were included. Intensive treatment, which reduced mean HbA1c by 0.9% on average, was associated with a significant reduction of incident cardiovascular events and myocardial infarction (OR 0.89 [0.83–0.95] and 0.86 [0.78–0.93], respectively), but not of stroke or cardiovascular mortality (OR 0.93 [0.81–1.07] and 0.98 [0.77–1.23], respectively). In meta-regression analysis, a higher BMI duration of diabetes, and incidence of severe hypoglycaemia were associated with greater risk for cardiovascular death in intensive treatment groups.

Conclusion

Intensified hypoglycaemic treatment in type 2 diabetic patients leads to a significant reduction of the incidence of myocardial infarction, while it does not affect the incidence of stroke and cardiovascular mortality. Hypoglycemia induced by intensified treatment could be associated with increased cardiovascular mortality.

Introduction

Type 1 and type 2 diabetes are associated with increased cardiovascular risk [1]. Furthermore, among diabetic patients, those with higher blood glucose and glycated hemoglobin (HbA1c) show a greater incidence of major cardiovascular events [2]. In type 1 diabetes, follow-up data from a large randomized clinical trial suggest that the improvement of metabolic control, obtained through intensive insulin treatment, can prevent cardiovascular disease in the long term [3]; similar results have been obtained in the long-term follow-up of the UK Prospective Diabetes Study (UKPDS), performed in type 2 diabetic patients [4]. Conversely, in type 2 diabetes, trials aimed at the assessment of the efficacy of lowering blood glucose in the prevention of micro- and macrovascular complications have always failed to detect a significant effect on cardiovascular events [5], [6], [7]; the only partial exception is represented by the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) [8], which showed a significant reduction of the incidence of some cardiovascular diseases, although it failed to reach the principal composite endpoint (death or major nonfatal cardiovascular events) for which it had been designed.

The negative results of those trials could have been determined by an insufficient sample size. In fact, the extent of risk reduction induced by lowering of HbA1c, as estimated by epidemiological studies [2], appears to be rather small; therefore, even large-scale trials could have had an insufficient statistical power to detect the effects of treatments. It should be considered that two of the largest trials [5], [7] were designed for a composite endpoint which included microvascular complications, and were therefore undersized for cardiovascular diseases as a separate endpoint; furthermore, another large trial [6], which was specifically designed for cardiovascular outcomes, had to be prematurely terminated because of an unexpected, significant difference in mortality between groups. The combination of the results of those trials could yield some relevant further information, which cannot be obtained by individual trials due to their insufficient statistical power.

Aim of this meta-analysis is the assessment of the effects of improvement of glycemic control on the incidence of cardiovascular diseases in patients with type 2 diabetes.

Section snippets

Methods

The study was performed according to the recommendations of the QUOROM statement [9].

Results

The Begg adjusted rank correlation test (Kendall tau, 0.20; p = 0.31) and the Egger regression approach (intercept, 0.406 [CI, –3.689 to 4.501]) suggested no major publication bias.

The process of retrieval of clinical trials is summarized in Appendix. Some large-scale trials were excluded, as they did not meet all inclusion criteria: HbA1c values were not reported in The University Group Diabetes Program (UGDP) [14], and between-group difference in mean HbA1c during follow-up did not reach the

Discussion

This meta-analysis shows that the improvement of metabolic control, obtained through the intensification of hypoglycemic therapy, reduces the incidence of cardiovascular disease in patients with type 2 diabetes. This result does not appear to be moderated by endpoint HbA1c in intensified treatment group, suggesting that improvement of metabolic control could be beneficial across a wide range of HbA1c values. This result is consistent with epidemiological data, showing an association of HbA1c

Acknowledgements

We gratefully acknowledge the technical support of Mrs Rossella Del Bianco in the preparation and revision of the manuscript.

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