The hypothesis that irrespective of the extent of the improvement of glycemic control, different glucose-lowering drugs may exert varying effects on cardiovascular risk profile has been repeatedly suggested. From available data, any overall harmful effect of metformin on the incidence of myocardial infarction, stroke, or heart failure has been ruled out, suggesting possible benefits in monotherapy and a detrimental effect when combined with sulfonylureas .
On the contrary, sulfonylureas, insulin, and thiazolidinediones have been suspected of adverse cardiovascular effects, although some data of specific drugs were not confirmed by subsequent investigations. A meta-analysis of retrospective cohort studies reported a significant excess risk for all-cause mortality associated with first-generation sulfonylureas . In observational studies, insulin therapy has been associated with increased cardiovascular morbidity and mortality, supporting the hypothesis of a proatherogenetic effect of insulin therapy in type 2 diabetes (18). On the other hand, the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial failed to detect any difference in cardiovascular effect of insulin in comparison with oral drugs (mainly metformin and sulfonylureas) in earlier stages of diabetes . Among thiazolidinediones, rosiglitazone has been withdrawn because of a supposed increase in the risk of myocardial infarction. On the other hand, pioglitazone seems to be considerably safer in this respect, and it could produce a glucose-independent reduction of cardiovascular risk , although it has been associated with increased risk of heart failure
Some of the newer drugs might be associated with cardiovascular benefits. In particular, meta-analyses of adverse events reported in available trials have shown significant reductions in cardiovascular morbidity after treatment with dipeptidyl peptidase-4 inhibitors , even when used in monotherapy . These meta-analytical findings should be considered with caution because they were obtained from trials designed for other purposes (usually efficacy on glucose control) without any clear definition of methods for screening and criteria for diagnosis of cardiovascular events. However, there is wide experimental evidence suggesting that incretin-based drugs could be associated with cardiovascular protection, even through glucose-independent mechanisms .
It is likely that individual drugs used for blood glucose control in type 2 diabetes can have different effects (either beneficial or detrimental) on cardiovascular risk, irrespective of their action on glycemia. This possibility complicates the analysis of results of available trials on the long-term effects of improvement of metabolic control. In some of the available studies, there was widespread use of drugs possibly associated with cardiovascular harm (e.g., rosiglitazone in ACCORD), which could have masked some of the benefits of lower HbA1c; conversely, in future trials, the use of drugs with glucose-independent beneficial actions may produce an overestimation of the protection conferred by strict metabolic control in type 2 diabetes.
Cons
The pathophysiology of accelerated atherosclerosis and CVD risk in diabetes is complex . Several risk factors for CVD, including insulin resistance/hyperinsulinemia, hyperglycemia, overweight/obesity, hemorreological abnormalities, dyslipidemia, and hypertension, are often present in varying combinations in patients with type 2 diabetes. Although some studies have shown that hyperglycemia is an independent risk factor for CVD in subjects with or without diabetes (1,27), the complex interaction of several risk factors justifies the difficulty in determining whether the treatment of hyperglycemia really improves the risk of macrovascular complications, as observed with microangiopathic complications. The role of nonglycemic factors that accompany the vast majority of patients with type 2 diabetes is much better understood and seems to be independent of glycemia. In addition, there have been studies demonstrating that interventions addressed to control these other factors in patients with diabetes effectively reduce cardiovascular risk . In contrast, to date, the positive effect of intensive glucose management in comparison with nonintensive glucose control on CVD outcomes is still far from proven.
The milestone study evaluating glucose control improvement and diabetes complications in type 1 diabetes is the DCCT (6). Because of the low rate of macrovascular events during the follow-up, the study lacked the power to evaluate the effect of glucose control on CVD . The DCCT/EDIC study followed up 1,341 initial participants evaluating cardiovascular events (17 years in total after entry in the DCCT). There was a 42% reduction for any cardiovascular event and a 57% reduction for cardiovascular death, myocardial infarction, or stroke in the group originally assigned to intensive management . The authors attributed this positive finding to the DCCT period of intensive glucose control despite an increase in body weight. While promising, these results need confirmation. We should not forget that CVD risk in long-standing type 1 diabetes may be related to weight gain (31,32) that may result from many years of sustained peripheral hyperinsulinemia. However, the latter may be less relevant than expected in determining CVD. Alternatively, higher rates of CVD in subjects with many years of type 1 diabetes, especially in older studies, really reflect the adverse effects of diabetic microangiopathy on CVD risk . It should also be considered that the impact of hyperglycemia on cardiovascular risk could be different in type 1 and type 2 diabetes. In a large Finnish study, an increment of 1 unit (%) of HbA1c increased cardiovascular mortality by 52% and 7% in type 1 and 2 diabetic subjects, respectively .
Among clinical trials assessing the long-term effect of diabetes treatment on CVD in type 2 diabetes, the UKPDS (8) was the largest one. In this study, no differences were observed for macrovascular disease: aggregate end points, including diabetes-related deaths, all-cause mortality, myocardial infarction, stroke, or amputations or death from peripheral vascular disease, did not reach statistical significance. Moreover, the cardioprotective action of metformin is based on the observations collected in a cohort of only 342 overweight patients with diabetes included in the UKPDS , which is a very small population compared with that of the most recent studies that have not been able to highlight a safe cardiovascular protective effect of intensive treatment.
In the PROactive study (3), it was claimed that the use of pioglitazone was associated with a positive and significant reduction in secondary composite end points of death, stroke, and myocardial infarction. However, in that study pioglitazone ameliorated other risk factors beyond blood glucose; a post hoc analysis suggests that HDL could have been a more important mediator of cardiovascular benefits than HbA1c .
More recently, in the ACCORD study >10,000 patients with type 2 diabetes at high risk for CVD were randomly assigned to intensive therapy (aimed at HbA1c ≤6.0%) or standard therapy (HbA1c goal of 7.0–7.9%). The results showed no significant difference in the primary end points (nonfatal myocardial infarction, nonfatal stroke, or death from CV causes) between the two groups, whereas all-cause mortality was 22% higher in the intensive therapy group (95% CI 1.01–1.46; P = 0.04). The causes of excess deaths in the ACCORD trial remain to be explained definitively. It is plausible, however, that excess mortality was due to serious hypoglycemia, which was significantly more frequent in the intensive control group.
In the ADVANCE study , ~11,000 patients with multiple CVD risk factors were followed for 5 years. The data showed that intensive glucose control (HbA1c goal <6.5%) did not provide greater macrovascular protection than did standard therapy. The VADT also did not show significant differences in the primary outcome, a first cardiovascular event (hazard ratio 0.88 [95% CI 0.74–1.05]; P = 0.14), or all-cause mortality (1.07 [0.81–1.42]; P = 0.62).
Furthermore, the results of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study (34) showed the difficulty of demonstrating beneficial effects of intensive glycemic control on CVD prognosis. There was no difference in the survival rate in the insulin-sensitization therapy versus the insulin provision group (88.2 vs. 87.9%, respectively; difference 0.3% [95% CI –2.2 to 2.9]; P = 0.89), despite a 0.5% difference in HbA1c (7.0 vs. 7.5%; P = 0.001).
In recent meta-analyses of phase 2 and 3 studies on a small number of events, the possibility was raised that some of the newer drugs, such as dipeptidyl peptidase-4 inhibitors and GLP-1 analogs, showed significant cardiovascular protective effects in type 2 diabetes , but these benefits could be due to vasculo- or cardioprotective actions (e.g., myocardial protection from ischemia, improvement of endothelial function, etc.), independent of glucose control .
The comparisons of results of different intervention studies are complex because of diversities in characteristics of enrolled subjects and in concomitant therapies. For example, the UKPDS trial was performed before the widespread use of statin therapy in type 2 diabetes and in subjects with newly diagnosed diabetes free from cardiovascular complications; conversely, PROactive, ACCORD, ADVANCE, and VADT enrolled subjects with high CVD risk. In fact, subgroup analyses of data from these trials suggested that patients with a shorter duration of diabetes, a lower HbA1c, or lack of established CVD might have benefited significantly from more intensive glycemic control .
More recently, the ORIGIN trial was designed to determine whether insulin can reduce cardiovascular morbidity in people with prediabetic hyperglycemia or early type 2 diabetes. Interestingly, in patients without prior CVD, insulin treatment was associated with a higher yearly incidence of CV events (2.21 vs. 1.89%), despite a similar glycemic control .
Few studies are available on the long-term CV effects of multifactorial interventions, in which treatment of hyperglycemia was associated with accurate therapy for associated risk factors. In the Steno-2 study (38), on a relatively small sample of subjects with type 2 diabetes, the intensive treatment of hyperglycemia, hypertension, dyslipidemia, and microalbuminuria reduced CV risk by >50%, demonstrating the need for a multifactorial intervention.
Presently, in type 2 diabetes, the use of statins, ACE inhibitors or angiotensin receptor blockers, and antiplatelet agents is an essential component of the clinical management. It is possible that the remarkable efficacy of other therapies in cardiovascular prevention makes it difficult to demonstrate an additional benefit of glucose-lowering interventions in clinical trials (38). For example, patients with CVD or CVD risk factors in the ACCORD, ADVANCE, and VADT trials also received statins, antihypertension agents, and aspirin as appropriate/needed, all of which have robust cardiovascular risk reduction properties.
Patients with type 2 diabetes are heterogeneous for age, duration of disease, comorbidity, and genetic background. Glucose-lowering therapy should be adapted to this complexity, with an attempt at improving, or at least avoidance of worsening, associated cardiovascular risk factors.
Conclusions
The assumption that treatment of hyperglycemia can prevent all diabetes complications, including CVD, has been an “act of faith” in the diabetological community for many decades. The contrasting results of available clinical trials in recent years have generated perplexity amid concerns that glucose-lowering therapies, under certain circumstances, might even be detrimental. When all available evidence to date is considered, which includes a fair number of large-scale clinical trials, the improvement of glycemic control appears to be associated with a reduction in the incidence of major cardiovascular events, whereas hypoglycemia could increase cardiovascular mortality. The pursuit of accurate glycemic control, avoiding both hyper- and hypoglycemia, should be recommended for preventing CVD in diabetes, and thus an individualized approach for achievement of target HbA1c in type 2 diabetic patients should be adopted (39,40). At the same time, it should also be clearly recognized that the control of other risk factors (such as hypertension and hypercholesterolemia) is more effective than glucose-lowering therapy in reducing the incidence of cardiovascular events. As a consequence, diabetes care implies a comprehensive management of cardiovascular risk, which includes other factors beyond glycemia.
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