Glucose Control and Cardiovascular Disease: Is it important? No

Hypertension and dyslipidemia, among other risk factors for CVD, are common in subjects with diabetes. Together, they can explain most, but not all, of the excess of risk of CVD in patients affected by the disease. High blood glucose has long been considered a risk factor for developing atherosclerosis, but data directly relating this alteration to the development and progression of CVD are conflicting. In this context, several glucose-lowering trials in both type 1 and type 2 diabetes showing significant reductions in microvascular complications have systematically failed to achieve significant reductions in macrovascular events (5). Nevertheless, it should also be mentioned that some systematic reviews and metanalysis performed in type 1 and type 2 diabetes (in the case of type 1 diabetes including some studies with few subjects and none or very small number of CV events) have suggested that attempts to improve glycemia reduce the incidence of CVD (9,10).

Before going through “proper” trials evaluating the effects of glycemic control and CVD, the results of the diabetes Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial require some comments (11,12). The DIGAMI trial demonstrated that a high-dose insulin infusion followed by 3 months of intensive subcutaneous insulin therapy was associated with a statistically significant reduction in mortality after a 12-month follow-up in patients with diabetes and an acute myocardial infarction (no significant differences in the primary end point at 3 months of follow-up). In the study, high doses of insulin infusion and high blood glucose targets were used during the acute phase of the protocol. Moreover, during the subcutaneous insulin treatment period and conventional clinical targets of glucose control, there were no differences in glucose values as expressed by A1C. Thus, DIGAMI strictly could not be considered a glucose-lowering trial supporting the beneficial effects of glucose control. In addition to this, the results of the unsuccessful DIGAMI-2 trial failed to find significant differences in A1C using different strategies on glucose management in type 2 diabetic subjects and acute myocardial infarction, as well as in mortality and CV outcomes (13). In conclusion, DIGAMI-2 did not provide additional information confirming or denying the beneficial effects of glucose control.

The University Group Diabetes Project (409 participants) may be considered the first glucose-lowering trial evaluating the CV effects of different strategies aimed at glucose control in type 2 diabetes (insulin addressed/not addressed to intensive control, phenformin, tolbutamide, and placebo) (14,15). After 12.5 years of follow-up, there were no differences in CVD events between the intensive control group with insulin, the nonintensive control insulin group, or the placebo. Phenformin and tolbutamide were discontinued because of the development of lactic acidosis and an excess of CV mortality, respectively.

In the Veterans Affairs Cooperative Study of Diabetes Mellitus (VACSDM), 153 subjects with type 2 diabetes were followed up for a mean of 2.25 years (16,17). This was a pilot feasibility trial in which patients under intensive glucose control (either with insulin or sulfonylureas) achieved a significant reduction in A1C (−2.1% absolute reduction). In spite of this, there was a nonsignificant trend toward an increase in CV events in the group under intensive control.

The Kumamoto study was designed to elucidate whether intensive glucose control (multiple injections of insulin) was associated with a decrease in the frequency (primary prevention) or severity (secondary prevention) of microvascular complications in 110 patients with type 2 diabetes (18). After 8 years and a 2.2% reduction in A1C, in the group receiving intensive control, there were positive results in both primary and secondary prevention of microvascular disease. After evaluating the effect of intensive treatment on CV events (cardiac, cerebrovascular, and peripheral), this was not significant, and this negative result was attributed to the small number of subjects included in the study by the authors.

Undoubtedly, the U.K. Prospective Diabetes Study (UKPDS) is still the landmark study evaluating the effects of glucose control on type 2 diabetes complications (19). Including more than 3,800 subjects, the study demonstrated a 12% significant reduction in a composite of micro- and macrovascular type 2 diabetes–related end points. However, it should be mentioned that UKPDS was underpowered to specifically assess the effect of improving glucose control on CVD. There was a nonsignificant reduction (16%) in the risk of MI and a statistically nonsignificant increase in the risk of stroke (Table 1). The positive effects of using metformin to improve glycemic control is a large claim because it was statistically associated with beneficial effects preventing any diabetes-related end point, diabetes-related mortality, and the frequency of MI (20). However, these results derived from a substudy of UKPDS were limited to overweight type 2 diabetic subjects.

The use of pioglitazone in type 2 diabetes (secondary prevention) has been evaluated in the PROspective pioglitAzone Clinical Trial In Macrovascular Events (PROactive) (21). It was claimed that the use of the drug was associated with a positive and significant reduction in a secondary composite end point of the study (death, stroke, and MI). Considering that the use of pioglitazone was associated not only with a reduction in A1C, but also triglycerides, the ratio of LDL to HDL, and blood pressure, whether the beneficial effects of pioglitazone were due to the improvement of glucose, to the amelioration of the other CVD risk factors, or to both remains to be elucidated (22).

The milestone study evaluating glucose control improvement and diabetes complications in type 1 diabetes is the Diabetes Control and Complications Trial (DCCT) (23). As a result of this study, intensive management of glycemia with multiple insulin doses is the gold-standard therapy in subjects with the disease to reduce the burden of microvascular complications (primary and secondary prevention). Because of the low rate of macrovascular events during the follow-up, the study lacked enough power to evaluate the effect of glucose control on CVD (24) (Table 1). The DCCT/Epidemiology of Diabetes Interventions and Complications (EDIC) study followed up 1,341 initial participants evaluating CV events (17 years in total after entry in the DCCT). There was a 42% reduction for any CV event and a 57% reduction for CV death, MI, or stroke in the group originally assigned to intensive management (25). In spite of the fact that the authors attributed this positive finding to the DCCT period of intensive glucose control, this piece of data from the DCCT/EDIC study was derived from an epidemiological and observational investigation. While exciting, these results are far from definitive.

The lack of positive effects of glycemic control on CVD complications in diabetes in the above-mentioned trials that, up to now have assessed this topic, could be due to different factors: low number of subjects included, low number of CV events, not lengthy enough follow-up, low efficacy of therapies that have been used, the degree to which glucose reduction might reduce CVD events has not been achieved, or just because the effect of glycemic control on CVD is superfluous in comparison with the effect of controlling other risk factors in diabetes. Under this context, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which was designed to determine whether intensively lowering blood glucose (below current recommendations) would reduce the risk of CV events or death from CVD, specifically in people with type 2 diabetes who were at a particularly high risk, recently has shown that this strategy is associated with an increased risk of death. Therefore, the degree to which glucose reduction may safely reduce CVD remains unclear.

In conclusion, currently, the relationship (if there is any) between glucose control and CVD in diabetes is still a matter of controversy. The results of the effect of intensive glucose control in comparison with usual management of major CV events are still inconclusive. In the meantime, an overall strategy toward risk management for our patients with type 1 and type 2 diabetes should place appropriate emphasis on blood pressure and lipid control to reduce the leading complications of diabetes.

No potential conflicts of interest relevant to this article were reported.