Whereas epidemiological and pathophysiological growing evidence demonstrated a direct link between hyperglycemia and cardiovascular morbidity and mortality in diabetic patients, the results of large clinical trials, investigating the efficacy of improving glycemic control in both type 1 and type 2 diabetes to reduce cardiovascular events, have not been convincing. The Diabetes Control and Complications Trial (DCCT) showed a trend toward a 41% risk reduction of cardiovascular events in type 1 diabetes . Moreover, during the posttrial 9-year follow-up observational period of the DCCT-Epidemiology of Diabetes Interventions and Complications (EDIC) trial, despite the loss of original difference in HbA1c as a consequence of conventional treatment switching to intensive approach and the less tight glycemic control in patients intensively treated, a risk reduction for any cardiovascular event (42%; P = 0.02) and for nonfatal myocardial infarction, stroke, or death for CVD (57%; P = 0.02) was fully achieved . Some conditions, such as the baseline young age of the study sample, the low mortality, and the cardiovascular incidence rate reported during the observation, may have contributed to reveal cardiovascular benefits in the long term only.
A benefit for long-term cardiovascular risk profile has also been described for type 2 diabetes. The UK Prospective Diabetes Study (UKPDS) reported a 16% reduction in the risk of myocardial infarction, with borderline statistical significance (P = 0.052) . In the 10-year posttrial follow-up, patients originally randomized to receive intensified glucose treatment achieved a significant reduction in the incidence of myocardial infarction (risk ratio reduction 15%; P = 0.0014) and all-cause mortality (13%; P = 0.007) (2). In the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) trial, which compared pioglitazone with placebo, with HbA1c difference of ~0.5%, a reduced risk for the main secondary end point—a composite of all-cause mortality, nonfatal myocardial infarction, and stroke (hazard ratio 0.84; P = 0.027)—was observed in the intervention group .
On the other hand, no significant improvement in cardiovascular risk was observed with intensification of diabetes therapy in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) and the Veterans Affairs Diabetes Trial (VADT) ; in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial , the reduction in cardiovascular morbidity in the intensified therapy group did not reach statistical significance, due to the premature interruption because of increased mortality. The negative results of these trials on cardiovascular events may have been determined by the insufficient sample size. It should be considered that one of these trials (i.e., ACCORD), which was specifically designed for cardiovascular outcomes, was prematurely interrupted (before reaching the target number of events) because of an unexpected excess of mortality in the intervention group, whereas two other studies (e.g., UKPDS and ADVANCE) were designed for a composite end point including macro- and microvascular complications, which obviously has a higher incidence than cardiovascular events alone, thus resulting in an undersized study sample for CVD as a separate end point.
When several insufficiently powered studies fail to provide clear results, they should be combined in a meta-analysis to retrieve relevant information, which would otherwise remain hidden because of statistical reasons. The efficacy of the improvement of glycemic control on the cardiovascular risk profile can be easily demonstrated by combining the results of all trials exploring cardiovascular end points and comparing treatment groups with an HbA1c difference of at least 0.5%. Intensified treatment for type 2 diabetes is associated with a significant reduction of all cardiovascular events (overall odds ratio 0.89; P = 0.001) and myocardial infarction (0.84; P < 0.001) . The reduction of cardiovascular morbidity induced by diabetes treatment should theoretically produce a decrease in cardiovascular mortality; however, no such improvement is observed when combining the results of large-scale trials (12). The lack of effect of improvement of glucose control on mortality is largely driven by the negative result of the ACCORD trial, with other studies (particularly UKPDS and PROactive) showing nonsignificant trends toward improvement. Excess mortality in ACCORD could be explained, in part, by the aggressive therapeutic approach in the intensified treatment group, thus leading to a remarkable increase of hypoglycemia. Intensive glycemic control is related to an increased hypoglycemic risk, as observed both in individual trials and in their meta-analysis. A positive correlation between incidence of severe hypoglycemia and cardiovascular mortality has been documented . There is evidence that hypoglycemia may adversely affect the cardiovascular risk profile, in particular in subjects affected by a longer duration of diabetes. Hypoglycemia triggers a cascade of physiologic effects, inducing adrenergic activation, oxidative stress, and cardiac arrhythmias, and may contribute to sudden death and ischemic cerebral damage (14). Overall, available trials show that reduction of hyperglycemia reduces the incidence of major cardiovascular events, whereas severe hypoglycemia may increase cardiovascular mortality. In fact, even in the acute phase of major cardiovascular events, a very aggressive treatment of hyperglycemia determining a high hypoglycemic risk increases mortality (15). If this is the case, hypoglycemia-inducing agents (such as insulin or sulfonylureas) could have a less favorable cardiovascular profile than glucose-lowering drugs, which do not induce hypoglycemia.
No comments:
Post a Comment