The Parodox of Glycemic Control and Cardiovascular Complications: Sorting Out the Data

The results of three recent trials, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the Action in Diabetes and Vascular Disease(ADVANCE) trial, and the Veterans Affairs Diabetes Trial (VADT), indicate that lower blood glucose levels are not always better. The major aim of all three randomized controlled trials was to determine whether lowering the blood glucose (hemoglobin A [A1C]) to normal or near-normal would _1creduce the occurrence of cardiovascular events. In the ACCORD trial,unexpected deaths in the intensive therapy (IT) group, over and above the number of deaths in the conventional therapy (CT) group, resulted in the early discontinuation of the trial.¹  There were no findings of increased mortality related to IT in the ADVANCE trial;however, preliminary analyses have found no reduction in rates of macrovascular events in the IT group.²  The VADT also found no difference in macrovascular event rates between IT and CT groups.³  Taken together, data from all three of these trials suggest there is no benefit of aggressive glycemic control on macrovascular complications in diabetic patients.

These outcomes leave many of us questioning what we thought we knew. Glycemic control as close to the normal range as possible purportedly simulates the nondiabetic state. It is well established that tight glycemic control reduces rates of microvascular complications in diabetic patients; why wouldn't the same hold true for macrovascular events and cardiovascular mortality? A closer look at these important clinical trials may clarify some points but may also leave us with further questions.

All three trials shared the aim of determining the relationship between glycemic control and macrovascular events (myocardial infarction and stroke);however, the study designs, populations, and outcomes were somewhat different. ACCORD randomized 10,251 patients with type 2 diabetes (mean age 62 years) and a baseline median A1C of 8.1%. IT was individualized by the investigators with the goal of rapidly and safely lowering A1C to < 6%. Combinations of glucose-lowering drugs were used in each group and included metformin,sulfonylureas, thiazolidinediones (TZDs), and insulin. Subjects in the IT group attended more frequent follow-up visits than the CT subjects. At 1 year,the CT group had achieved a median A1C of 7.5%, compared to the IT group,which achieved a median A1C of 6.4%. Subjects were subsequently followed for a total of 3.5 years, during which the A1C levels remained relatively stable.¹ 

The ADVANCE trial randomized 11,140 patients with type 2 diabetes (mean age 67 years) and a baseline mean A1C of 7.5% to one of two groups (IT or CT). The goal of the IT arm was to lower the A1C to 6.5%. Subjects in the IT group were given modified-release gliclazide (all other sulfonylureas were discontinued),as well as additional treatments suggested by the study protocol at the discretion of the treating provider. The combination of medications used in both groups included metformin, sulfonylureas, TZDs, acarbose, and insulin. As in ACCORD, subjects in the IT group attended more frequent visits than those in the CT group. After 5 years of follow-up, the mean A1C was 7.3% in the CT group and 6.5% in the IT group.² 

The most recent of the three trials is the VADT, completed only days before its findings were released at the American Diabetes Association (ADA)68^th Annual Meeting and Scientific Sessions in San Francisco in June of this year. The VADT randomized 1,791 U.S. veterans (97% male, mean age 60 years) to IT versus CT with a baseline mean A1C of 9.5%. The goal of the IT group was to decrease A1C to < 7%. The majority of subjects received several drugs in combination, including metformin, rosiglitazone, glimepiride,and insulin. After 6.5 years of follow-up, the mean A1C was 8.4% in the CT group and 6.9% in the IT group.⁴ 

Of the three trials, only ACCORD found an increase in rates of cardiovascular events and death associated with intensive therapy. The trial was stopped prematurely because of this finding.¹  In ADVANCE and VADT, investigators found no difference in mortality or cardiovascular outcomes between groups.^2,3 Hypoglycemia was problematic, to some extent, in all three trials. In ACCORD,16% of subjects in the IT group experienced hypoglycemia requiring assistance versus 5.1% in the CT group, although only one death in each group was identified as “probably” related to hypoglycemia.¹  In ADVANCE, 2.7% of subjects in the IT group had at least one severe episode of hypoglycemia compared to 1.5% in the CT group. These findings included one fatal episode in the IT group and one episode in each group causing permanent disability.²  In the VADT, severe hypoglycemia occurred in 21% of subjects in the IT group versus 10% in the CT group. In addition, the VADT found that an episode of severe hypoglycemia within 3 months before a cardiovascular event was a strong predictor (second only to a previous event) of the event.³ 

Depending on the severity of the episode and pre-existing comorbidities,hypoglycemia may trigger myocardial infarction, stroke, and ventricular arrhythmias.^5,6 A low level of glucose in the blood stimulates sympathetic neural activation as well as catecholamine secretion, resulting in an increased heart rate,blood pressure, and overall workload on the heart.⁷ Additionally, as a result of these hemodynamic changes, shear stress in the arterial wall may contribute to destabilization of atherosclerotic plaque⁸  and possibly precipitate an atherothrombotic event. Severe episodes of hypoglycemia usually occur in patients who lack early warning signs. Hypoglycemia unawareness,usually ascribed to patients with type 1 diabetes, may similarly affect patients with type 2 diabetes. In a sub-study of the Treating to Target in Type 2 Diabetes study,⁹  112 subjects taking one of three different insulin regimens were given continuous glucose monitoring systems. The investigators found that asymptomatic low blood glucose levels (< 56 mg/dl) occurred 40 times more frequently than self-reported hypoglycemia episodes. Surprisingly, most episodes occurred in the daytime.¹⁰ 

Duration of type 2 diabetes seems to be predictive of hypoglycemia awareness and the severity of hypoglycemic episodes. In a small clinical study, the counterregulatory responses to hypoglycemia were examined in nondiabetic subjects and compared to two groups of subjects with type 2 diabetes. One group of diabetic subjects was controlled with sulfonylureas,suggesting the presence of endogenous insulin secretion associated with a shorter duration of disease. The second group of diabetic subjects was insulin deficient as evidenced by low serum C-peptide levels. The counterregulatory response to hypoglycemia was intact in the nondiabetic subjects and those controlled with sulfonylureas but almost absent in the insulin-deficient type 2 diabetic patients.¹¹  Other investigators have found that treatment with insulin for > 10 years is a predictor of increased risk of severe hypoglycemia in type 2 diabetes.¹²  In addition, when patients with type 2 diabetes become insulin deficient, they experience severe hypoglycemia at a frequency approaching that of patients with type 1 diabetes.¹³  Along with the findings from recent clinical trials, these data suggest that, at least in patients with longstanding type 2 diabetes, hypoglycemia may be a more serious problem than previously appreciated.

Although no cardiovascular benefit was found when IT groups were compared to CT groups, the diversity of baseline glycemic control, pre-existing comorbidities, and duration of diabetes in these subjects merits exploration. In the ACCORD trial, data suggested that patients with a lower baseline A1C and those without cardiovascular disease may derive benefit from intensive glucose lowering, although the study was not designed to test this hypothesis.¹  In the VADT, there was a significant relationship between longer duration of diabetes and risk of cardiovascular events. Subjects who had diabetes for < 7 years appeared to gain cardiovascular benefit from IT, whereas those with the longest duration of diabetes (up to 24 years) were found to have excess cardiovascular risk and did not benefit from intensive therapy.³ 

There are several key messages to take away from these important clinical trials. We now have even more evidence that aggressive treatment early in the course of type 2 diabetes is warranted. The negative outcomes in these studies occurred in subjects with the longest duration of diabetes, the highest baseline A1Cs, and the strongest history of pre-existing cardiovascular disease.

Even from clinical experience, it is apparent that type 2 diabetes of long duration is, in many ways, a different disease than early type 2 diabetes. A 45-year-old man with new-onset type 2 diabetes, an A1C of 8%, and mild dyslipidemia and hypertension may benefit greatly from a very aggressive approach targeting lipids, blood pressure, and blood glucose, as well as providing lifestyle counseling and anti-platelet therapy. Lowering his A1C to a normal or near-normal level with a combination of support with weight loss and exercise in addition to pharmacological therapy may greatly reduce his risk of a future cardiovascular event.

Because he is early in his disease process, he could probably achieve all of these goals without needing a regimen that would put him at risk for hypoglycemia. If he were, by virtue of his medication regimen, at risk for hypoglycemia, he would have an intact counterregulatory system that would make hypoglycemia unawareness and severe hypoglycemia highly unlikely.

In contrast, consider a different patient with an A1C of 8%. This is a 75-year-old man with a 20-year duration of type 2 diabetes, on insulin > 10 years, a history of coronary artery disease with prior stent placement, and suboptimally treated dyslipidemia and hypertension. In this patient, lowering A1C to 7% or even 7.5% may be acceptable and less risky than attempting a near-normal glycemic target.

Ten years ago, the U.K. Prospective Diabetes Study provided evidence that well-controlled blood pressure was more effective than tight glycemic control in the prevention of macrovascular complications in patients with type 2 diabetes.^14,15 Other pivotal clinical trials of the past decade demonstrated coronary heart disease risk reduction associated with lipid lowering^16,17 and anti-platelet therapy¹⁸  in diabetic patients. Because of the widespread dissemination of these data and successful translation into clinical practice, our patients with type 2 diabetes have benefited from reduced cardiovascular risk.

Indeed, the good news from these recent clinical trials is that the incidence of cardiovascular events in all of the groups studied was much lower than predicted from previous epidemiological data. In ACCORD, subjects in both groups had lower mortality than reported in studies of similar patients.¹  The annual rate of macrovascular events in ADVANCE was lower than anticipated based on previous studies of patients with type 2 diabetes, and the authors suggest the greater use of statins, anti-hypertensive medications, and anti-platelet agents as the likely reason. In the VADT, the event rate was less than one-third of what was predicted.³  These lower overall event rates indicate that most subjects had already achieved optimal cardiovascular risk reduction.

A review of the current ADA standards of medical care¹⁹  will confirm that these recommendations are still relevant and, in fact, may be even more relevant given recent findings. In particular, recommendations for A1C lowering appear to be right on target. The 2008 recommendations state a goal of < 7% for nonpregnant adults in general and as close to normal (< 6%)as possible without significant hypoglycemia in selected patients. There are less stringent A1C goals in high-risk patients (those with a history of severe hypoglycemia, comorbid conditions, longstanding diabetes, and cardiovascular complications). Table 1 lists current recommendations for blood pressure and lipids as well.¹⁵ 

Future clinical trials will focus on questions that arose from the seemingly paradoxical results of ACCORD, ADVANCE, and VADT. For now, despite the apparent controversy, clinicians can be confident that the treatment we have been prescribing and recommending for our patients is safe and effective.