Prevention of cardiovascular disease through glycemic control in type 2 diabetes: A meta-analysis of randomized clinical trials
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.
References (38)
- et al.
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) The QUORUM statement
Lancet
(2000)- et al.
Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature
J Clin Epidemiol
(2000) - et al.
Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study
Diabetes Res Clin Pract
(1995) - et al.
Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73
J Diabetes Complications
(2006) - et al.
Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials
Lancet
(2007) - et al.
Multimorbidity due to diabetes mellitus and chronic kidney disease and outcomes in chronic heart failure
Am J Cardiol
(2009) - et al.
Thiazolidinediones and cardiovascular risk: will the evidence so far available modify treatment strategies for type 2 diabetes?
Nutr Metab Cardiovasc Dis
(2008) - et al.
Future perspectives on glucagon-like peptide-1, diabetes and cardiovascular risk
Nutr Metab Cardiovasc Dis
(2008) - et al.
Similarity of the impact of type 1 and type 2 diabetes on cardiovascular mortality in middle-aged subjects
Diabetes Care
(2008)
Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus
Ann Intern Med
Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes
N Engl J Med
10-year follow-up of intensive glucose control in type 2 diabetes
N Engl J Med
Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes
N Engl J Med
Effects of intensive glucose lowering in type 2 diabetes
N Engl J Med
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group
Lancet
Meta-analysis: principles and procedures
BMJ
Operating characteristics of a rank correlation test for publication bias
Biometrics
Bias in meta-analysis detected by a simple, graphical test
BMJ
Cited by (178)
Exploring the Underlying Mechanisms Linking Adiposity and Cardiovascular Disease: A Prospective Cohort Study of 404,332 UK Biobank Participants
2023, Current Problems in CardiologyDiabetes mellitus is associated with a higher relative risk for venous thromboembolism in females than in males
2022, Diabetes Research and Clinical PracticeEffects of insulin on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials
2022, Nutrition, Metabolism and Cardiovascular DiseasesCitation Excerpt :On the other hand, clinical trials with drugs with a greater insulin-sensitizing effect than metformin, such as pioglitazone, provided conflicting results with respect to cardiovascular risk [48–51]. Cardiovascular risk is strongly associated with HbA1c levels [52] and the amelioration of glycemic control has been demonstrated to reduce the incidence of MACE [53–55]. Insulin, particularly in the short/medium-term [56], is an effective glucose-lowering agents; however, insulin therapy increases the risk of hypoglycaemia, that could be associated with a higher risk of cardiovascular mortality [54].
Italian guidelines for the treatment of type 2 diabetes
2022, Nutrition, Metabolism and Cardiovascular DiseasesCitation Excerpt :Adherence to this guideline can be assessed by estimating the proportion of patients at HbA1c target in existing databases [11,12]
Cardiovascular events and all-cause mortality in patients with type 2 diabetes treated with dipeptidyl peptidase-4 inhibitors: An extensive meta-analysis of randomized controlled trials
2021, Nutrition, Metabolism and Cardiovascular Diseases