Diabetes management: More than just cardiovascular risk?

United Kingdom Prospective Diabetes Study

A second major trial, the United Kingdom Prospective Diabetes Study (UKPDS),⁸ assessed the effect of excellent diabetes control on diabetes complications in patients with type 2 diabetes. A total of 3,867 patients newly diagnosed with type 2 diabetes, median age 54, who after 3 months of diet treatment had mean fasting plasma glucose concentrations of 110 to 270 mg/dL, were randomly assigned to an intensive policy (with a sulfonylurea or insulin or, if overweight, metformin) or a conventional policy with diet. The aim in the intensive group was a fasting plasma glucose less than 108 mg/dL. In the conventional group, the aim was the best achievable fasting plasma glucose with diet alone; drugs were added only if there were hyperglycemic symptoms or a fasting plasma glucose greater than 270 mg/dL.

Over 10 years, the median hemoglobin A_1c level was 7.0% (interquartile range 6.2%–8.2%) in the intensive group compared with 7.9% (6.9%–8.8%) in the conventional group. Compared with the conventional group, the risk of any diabetes-related end point was 12% lower in the intensive group (95% CI 1%–21%, P = .029), the risk of any diabetes-related death was 10% lower (−11% to 27%, P = .34), and the rate of all-cause mortality was 6% lower (−10% to 20%, P = .44). Most of the reduction in risk of any diabetes-related end point was from a 25% risk reduction (95% CI 7%–40%, P = .0099) in microvascular end points, including the need for retinal photocoagulation.

UKPDS long-term follow-up

In 2008, Holman et al published the results of long-term follow-up of patients included in the UKPDS.⁶ In posttrial monitoring, 3,277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires.

Between-group differences in hemoglobin A_1c levels were lost after the first year. However, in the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P = .04) and microvascular disease (24%, P = .001), while risk reductions for myocardial infarction (15%, P = .01) and death from any cause (13%, P = .007) emerged over time as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P = .01), myocardial infarction (33%, P = .005), and death from any cause (27%, P = .002).

The long-term follow-up to the UKPDS, like the long-term follow-up to the DCCT, demonstrated metabolic memory: that is, despite an early loss of glycemic differences after completion of the trial, a continued reduction in microvascular risk and an emergent risk reduction for myocardial infarction and death from any cause were observed.

These long-term randomized prospective trials in patients with type 1 and type 2 diabetes clearly show that the glucose hypothesis is in fact correct: intensive glucose control lowers the risk of both microvascular and macrovascular complications of diabetes.

IS THERE DISCORDANCE BETWEEN OLDER AND MORE RECENT TRIALS?

If the results of these older landmark clinical trials are true, why did the more recent clinical trials fail to show cardiovascular benefit with stricter glycemic control, and in one trial² demonstrate the potential for harm? (ACCORD² found an increased death rate in patients who received intensive therapy, targeting a hemoglobin A_1c below 6.0%.)

The answer lies in the populations studied. ACCORD,² VADT,³ and ADVANCE⁴ were performed in older patients with prior cardiac events or with several risk factors for cardiovascular events. The study populations were picked to increase the number of cardiac events in a short time frame. Therefore, extrapolating the results of these studies to the younger population of patients with diabetes, most of whom have yet to develop macrovascular disease, is inappropriate.

The available evidence suggests that early aggressive management of diabetes reduces the risk of macrovascular disease, but that this benefit is delayed. In the UKPDS and DCCT trials, it took 10 to 17 years to show cardiac benefit in younger patients.

The results of ACCORD,² VADT,³ and ADVANCE⁴ are important when considered in the correct clinical context. Two of these trials did demonstrate some microvascular benefit as a result of better glycemic control in older patients, many of whom had longstanding diabetes. These studies suggest that, in patients who already have established cardiovascular disease or have several risk factors for cardiovascular events, a less-strict glycemic target may be warranted.

These trials should not be interpreted as saying that glycemic control is unimportant in older patients at higher risk. Rather, they suggest that an individualized approach to diabetes management, supported by the most recent American Diabetes Association guidelines,⁹ is more appropriate.

Physicians may reasonably suggest a stricter A_1c goal (ie, < 6.5%) in certain patients if it can be achieved without significant hypoglycemia. Stricter glycemic targets would seem appropriate in patients recently diagnosed with diabetes, those who have a long life expectancy, and those who have not yet developed significant cardiovascular disease.⁹

However, in patients who already have developed advanced microvascular and macrovascular complications, who have long-standing diabetes, who have a history of severe hypoglycemia (or hypoglycemia unawareness), or who have a limited life expectancy or numerous adverse comorbidities, a less strict glycemic target (hemoglobin A_1c < 8%) may be more appropriate.⁹