Despite a better understanding of cardiovascular risk factors and attempts at optimal management, diabetes-related macrovascular events remain a significant cause of morbidity and mortality in the United States and worldwide. The trials to date have validated strict glycemic control as a method to achieve sustained reductions in the rate of nephropathy, neuropathy, and retinopathy due to diabetes. For these microvascular complications, the closer hemoglobin A1c is to normal levels, the better the outcome. Although reducing hemoglobin A1c levels to 7% has been shown to reduce macrovascular events, demonstrating an additional reduction in macrovascular events with tighter glycemic control has been more difficult to achieve. A careful review of recent trials, however, has demonstrated that treatment early in the disease course and the ability to safely maintain lower hemoglobin A1c levels might be critical factors in further reducing macrovascular events. In conclusion, with the introduction of novel antidiabetic agents, future trials using these drugs might be able to definitively establish the safety and efficacy of reducing cardiovascular events with stringent glycemic control; however, the current evidence is inconsistent.
Defined as a glycated hemoglobin A1c (HbA1c) level of ≥6.5%, fasting plasma glucose of ≥126 mg/dl, or a 2-hour plasma glucose of ≥200 mg/dl after an oral glucose tolerance test, diabetes has an estimated prevalence in the United States population of 12.9% in adults. However, with consideration of prediabetic states, defined as impaired fasting glucose or impaired glucose tolerance, ≤40% of the population exhibits evidence of a hyperglycemic state. Despite increased awareness screening, diabetes remains a major cause of devastating vascular complications, including heart disease, stroke, blindness, and nontraumatic amputations, and ≤7 million persons in the United States remain undiagnosed.
Macrovascular disease remains the leading cause of mortality in patients with type 1 and type 2 diabetes. The current recommended strategies that aim to reduce this risk use a multifactorial treatment approach that includes glycemic control, in conjunction with low-density lipoprotein lowering and blood pressure lowering strategies. The effectiveness of this strategy is perhaps best illustrated by the results from the Steno-2 study, in which patients with type 2 diabetes and persistent microalbuminuria were randomized to receive intensive multifactorial risk reduction, defined as a HbA1c level of ≤6.5%, along with specific cholesterol and blood pressure targets. These patients experienced a near 50% reduction in the risk of death and a 60% reduction in cardiovascular (CV) events compared with “conventional” treatment. The precise contribution of glycemic control to this risk reduction could not be directly determined from their study. The current guidelines from the American Diabetes Association have recommended a target HbA1c of <7% as “reasonable” for most patients, suggesting that better glycemic control might prevent the micro- and macrovascular complications of the disease. Trials examining glycemic control have revealed that although the risk of microvascular outcomes is significantly reduced by achieving strict glycemic targets, the same does not hold true for macrovascular outcomes.
Epidemiology of Increased CV Risk
It is essential to underscore the extent and nature of the increased CV risk that stems from hyperglycemia, even in the earliest stages of the disease. Data from the Nurses’ Health Study, which included 117,629 healthy women, demonstrated that women who developed diabetes during 20 years of follow-up had a relative risk of 2.8 for myocardial infarction or stroke. An elevated risk was seen beginning 15 years preceding the actual diagnosis of diabetes. A study examining the relation between the 2-hour postural glucose loading results and coronary heart disease (CHD) mortality for 33 years in 17,869 men found that, beginning at a seemingly normal glucose level of 83 mg/dl, a near linear relation was found between an increasing serum glucose level and CHD mortality. Similar evidence for an increase in CHD and all-cause mortality was demonstrated using data from the European Prospective Investigation into Cancer Study–Norfolk cohort (EPIC-Norfolk) study, in which an increased risk was noted in patients with a HbA1c of 5% to 5.4%.
Taken together, these epidemiologic studies have all emphasized that even the earliest stages of nascent hyperglycemia confer a greater risk of adverse CV outcomes. The incremental risk as the HbA1c increases was quantified by a recent meta-analysis. That study that reported that for every 1% increase in HbA1c, the risk of any CHD event, a fatal CHD event, or stroke increased by 13%, 16%, and 17%, respectively, although the analysis did not account for the use of diabetes medications.
The putative mechanisms by which hyperglycemia mediates vascular complications are extensive and varied. The formation of advanced glycation end products (AGE), stimulation of proinflammatory molecules, impaired endothelial function, impaired fibrinolysis, and platelet dysfunction have all been proposed as contributing or accelerating factors for atherosclerotic disease. This interplay could account for the correlation between CV risk and glucose levels less than the diabetic range.
During hyperglycemic states, irreversible nonenzymatic glycation of proteins leads to formation of AGE. The effects of AGE include deposition in the extracellular space and disruption of the vessel wall, where it can trap low-density lipoprotein and increase its susceptibility to oxidation. Additionally, through a receptor-mediated cell signaling pathway, AGE can induce oxidative stress and result in upregulation of NF-κB to activate transcription of several proinflammatory factors (e.g., tumor necrosis factor-α, interleukin-1, interleukin-6, cell adhesion molecules), all of which have been implicated in atherosclerosis. Hyperglycemia also attenuates endothelium-dependent vasodilation, with in vitro studies suggesting dysfunction occurs because of imbalances between endothelial nitric oxide synthase and nitric oxide production and by the generation of reactive oxygen species. In vivo studies, such as the Northern Manhattan Study (NOMAS), demonstrated that flow-mediated dilation, a measure of endothelial function, was decreased in subjects when the fasting glucose levels were >100 mg/dl, further supporting the hypothesis that subtle hyperglycemia can have immediate effects on the endothelium. A unifying mechanism for this endothelial dysfunction might be mediated by elevations in protein kinase C, which occurs in hyperglycemic states. Protein kinase C is responsible for phosphorylation of endothelial nitric oxide synthase to allow nitric oxide synthesis and might have activating effects on NF-κB, further propagating vascular dysfunction and inflammation.
Plasminogen-activator inhibitor-1 is a serine protease that inhibits fibrinolysis and is upregulated in the setting of hyperglycemia. Together with the increased platelet aggregation seen in type 2 diabetes, elevated plasminogen-activator inhibitor-1 levels tilt the milieu toward a prothrombotic state. Both plasminogen-activator inhibitor-1 expression and platelet reactivity can be ameliorated by glycemic control, which has been shown in smaller human studies. Thus, although some of the mechanisms of hyperglycemia will leave an indelible effect on the vasculature, such as with AGE products, others can be diminished, or perhaps arrested, with improved glycemic control.
Glycemic Control and Microvascular Events: Reaping the Long-Term Benefits
Extensive data support glycemic control as an intervention to reduce the burden of microvascular disease. The United Kingdom Prospective Diabetes Studies (UKPDS) followed a multiethnic group of 5,102 subjects with newly diagnosed type 2 diabetes, who were randomized to conventional treatment through dietary restriction versus intensive treatment with either a sulfonylurea-insulin combination or metformin for a subset of overweight patients. Intensive control significantly reduced the incidence of microvascular events, with an estimated 37% reduction in retinopathy, neuropathy, and nephropathy for every 1% decrease in the HbA1c level (p <0.0001). In the post-trial monitoring, which followed up patients for ≤10 years, the patients in the intensive treatment arm continued to experience a significant reduction in microvascular outcomes (p = 0.0001). Similar dramatic results were demonstrated in the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes. The post-trial observations, a part of the Epidemiology of Diabetes Intervention and Complications (EDIC) study, demonstrated a 50% relative reduction in nephropathy (p = 0.006) for ≤16 years after the cessation of intensive glycemic control. These results support that the early initiation of glycemic control can have lasting benefits for microvascular disease, deemed the “legacy effect.”
Glycemic Control and Microvascular Events: Reaping the Long-Term Benefits
Extensive data support glycemic control as an intervention to reduce the burden of microvascular disease. The United Kingdom Prospective Diabetes Studies (UKPDS) followed a multiethnic group of 5,102 subjects with newly diagnosed type 2 diabetes, who were randomized to conventional treatment through dietary restriction versus intensive treatment with either a sulfonylurea-insulin combination or metformin for a subset of overweight patients. Intensive control significantly reduced the incidence of microvascular events, with an estimated 37% reduction in retinopathy, neuropathy, and nephropathy for every 1% decrease in the HbA1c level (p <0.0001). In the post-trial monitoring, which followed up patients for ≤10 years, the patients in the intensive treatment arm continued to experience a significant reduction in microvascular outcomes (p = 0.0001). Similar dramatic results were demonstrated in the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes. The post-trial observations, a part of the Epidemiology of Diabetes Intervention and Complications (EDIC) study, demonstrated a 50% relative reduction in nephropathy (p = 0.006) for ≤16 years after the cessation of intensive glycemic control. These results support that the early initiation of glycemic control can have lasting benefits for microvascular disease, deemed the “legacy effect.”
Glycemic Control and Macrovascular Outcomes: An Elusive Benefit, If at All?
Despite the improvements in microvascular end points, the results from several clinical trials have questioned the notion that macrovascular outcomes can be significantly altered by achievement of strict glycemic control. Not all the studies have proved inconclusive regarding CV outcome reductions. Long-term follow-up of the participants in the UKPDS demonstrated significant and persistent reductions in the risk of myocardial infarction (15%; p = 0.01) and all-cause mortality (13%; p = 0.007) for the sulfonylurea-insulin group, with even greater risk reductions in these events for patients in the metformin arm (33% and 27%, respectively). Using the carotid intima-medial thickness as a surrogate for atherosclerosis in the DCCT/EDIC population, a recent study demonstrated that the subjects in the intensive therapy group experienced a slower progression of carotid intima-medial thickness compared with the conventional therapy group, although the effect was attenuated in the latter 6 years of follow-up and by adjustment for systolic blood pressure.
Acarbose, an α-glucosidase inhibitor, was studied in a prediabetic population in the Study to Prevent [noninsulin-dependent diabetes mellitus] NIDDM (STOP-NIDDM) and found to reduce the rate of CV events by 53%. Also, a meta-analysis similarly supported significant reductions in the risk of myocardial infarction (MI) (hazard ratio 0.36, 95% confidence interval 0.16 to 0.80, p = 0.012) and any CV event (hazard ratio 0.65, 95% confidence interval 0.48 to 0.88, p = 0.006). Additionally, a recent randomized study of metformin versus glipizide in patients with coronary artery disease found that metformin use was associated with a 46% reduction in the risk of a composite of CV events, despite achievement of similar HbA1c levels (7%) in both arms at the conclusion of the follow-up period.
Three recent major trials—Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE), and Veterans Affairs Diabetes Trial (VADT)—sought to examine the benefit on macrovascular outcomes with intensive glycemic control. The VADT and ACCORD were both unable to prove their primary end point, a composite of major CV events. Also, although the ADVANCE study had a significant reduction it its primary end point, this benefit was largely driven by reductions in microvascular outcomes. Compared with earlier trials, the patients in the ACCORD, ADVANCE, and VADT were older, had had a diagnosis of diabetes for longer, and were deemed to have, or be at risk of, vascular disease ( Table 1 ). Although ADVANCE and VADT did not note differences in mortality, ACCORD, in particular, received a significant amount of attention for an increase in mortality at 1 to 2 years observed in patients in the intensive arm. The ACCORD patients in the intensive arm were therefore transitioned to standard therapy and followed up for a mean of 5 years. Interestingly, a reduction was seen in the secondary end point of nonfatal MI (hazard ratio 0.76, p = 0.004) for the patients in the intensive therapy arm that was counterbalanced by the increased mortality risk. Several subgroup analyses have been performed to better define which patients in ACCORD might have accounted for the increased risk in mortality. One study demonstrated that the risk of death was greater for patients in the intensive therapy arm when their respective HbA1c level was >7%, well above their target, although an HbA1c of 7% can represent consistent control or a combination of hypoglycemia and hyperglycemia. Another analysis suggested that although hypoglycemic episodes were unlikely to be the etiology of the increased mortality risk, it was perhaps the factors related to patient noncompliance or difficult to control hyperglycemia that resulted in the greater risk of death. Additional possible explanations for the increase in mortality risk could be the greater use of sulfonylureas in the intensive therapy arm or that despite the reduced risk of nonfatal MI with intensive therapy, the patients experiencing an MI were more likely to die from it.
| Variable | Accord | Advance | VADT |
|---|---|---|---|
| Mean age (yrs) | 62 | 66 | 60 |
| Mean DM duration (yrs) | 10 | 8 | 11.5 |
| Mean follow-up (yrs) | 3.5 | 5 | 5.6 |
| Intensive group | |||
| Target HbA1c (%) | <6 | <6.5 | <6 |
| Mean achieved HbA1c (%) | 6.4 | 6.4 | 6.9 |
| Standard group | |||
| Target HbA1c (%) | 7–7.9 | “Standard” | 8–9 |
| Mean achieved HbA1c (%) | 7.5 | 7 | 8.4 |
| Primary outcome results | |||
| All-cause mortality | |||
| HR | 1.22 | 0.93 | 1.07 |
| 95% CI | 1.01–1.46 | 0.83–1.06 | 0.81–1.42 |
| p Value | 0.04 | 0.28 | 0.62 |
| Nonfatal MI | |||
| HR | 0.76 | 0.98 | 0.82 |
| 95% CI | 0.62–0.92 | 0.77–1.22 | 0.59–1.14 |
| p Value | 0.004 | Not reported | 0.24 |
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