Does intensive therapy of type 2 diabetes help or harm? Seeking accord on ACCORD
ABSTRACTThe Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial tested the hypothesis that intensive glucose-lowering (with a hemoglobin A1c target of less than 6.0%) would reduce the incidence of atherosclerotic disease events and death compared with standard treatment (with a hemoglobin A1c target of 7.0% to 7.9%) in more than 10,000 patients with type 2 diabetes at high risk of cardiovascular events. The study was terminated early because more people had died in the intensive-treatment group than in the standard-treatment group (257 vs 203). The ACCORD results should not substantially alter our usual approach to glucose-lowering, which should still be “as low as we can get it safely” while avoiding hypoglycemia, significant weight gain, complex regimens, and, perhaps, the “stress” of maintaining glycemic control, especially in patients at high risk of coronary heart disease.
KEY POINTS
- No obvious cause, including hypoglycemia proximate to death or the use of any particular medication, clearly explained the excess deaths, although hypoglycemia occurred more often in intensively treated participants.
- The death rates in ACCORD were lower than in population studies and in other intervention trials. It is likely that multiple approaches to reducing the risk of cardiovascular disease contributed to this low mortality rate.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial1–5 was designed primarily to address, in patients with type 2 diabetes at high risk of cardiovascular events, whether intensive glucose control would result in a lower risk of atherosclerotic disease events or death than would standard treatment.
It was widely expected that intensive treatment would confer either modest benefit or, at worst, no benefit. However, the glucose-lowering arm of the trial was terminated early because of a higher mortality rate in the intensively treated group. (The ACCORD trial has two other arms, which concern blood pressure and lipid-lowering, and these are continuing.)
In earlier trials in type 2 diabetes, concerns had been raised about an increased risk of cardiovascular events and possibly death associated with glucose-lowering drugs, hypoglycemia itself, or both, and these were well known when ACCORD was convened. ACCORD was very carefully designed and included careful adjudication of each cardiovascular event and death, including whether hypoglycemia might have been a proximate cause of some sudden deaths.5
Therefore, the surprising result of the higher mortality rate with intensive glycemic control in ACCORD will be fodder for discussion in many arenas over the next several years, and it poses some challenges for physicians and patients in determining treatment goals, as well as for organizations that write clinical practice guidelines (and perhaps organizations involved in pay-for-performance based on these guidelines).
Still, I believe that the ACCORD results should not substantially change our approach to treatment goals in type 2 diabetes, although hemoglobin A1c targets below 6% may not have much added value for cardiovascular risk reduction. The low overall mortality rate in all the arms of the ACCORD trial emphasizes the importance of lifestyle modification, lipid and blood pressure therapy, and encouragement of aspirin use in all patients with type 2 diabetes.
This article reflects my views as a practicing diabetologist and clinical trialist (I was an investigator in the ACCORD trial) with a long-standing interest in clinical trials and in how the results influence clinical practice. The views I express herein may not reflect the views of other ACCORD investigators, the National Heart, Lung, and Blood Institute (NHLBI), the ACCORD trial coordinating center at Wake Forest University, or its data safety and monitoring board.
RISK OF CORONARY DISEASE INCREASES WITH GLUCOSE
Many observational studies6–10 have shown that the risk of cardiovascular disease, especially coronary heart disease, is two to five times higher in people with diabetes mellitus than in people without diabetes. The risk appears to be continuous, so the higher one’s glucose or hemoglobin A1c, the higher the risk.6 This risk even extends to glucose values well below the threshold values currently used to diagnose diabetes mellitus.6 Since there is no glucose threshold for coronary heart disease, the term dysglycemia (rather than hyperglycemia) has been proposed to note the relationship between glucose and coronary heart disease. (The glucose threshold for microvascular complications of diabetes, such as retinopathy and nephropathy, appears to be between 110 and 126 mg/dL).
The clustering of multiple coronary risk factors such as obesity, dyslipidemia, and hypertension has always raised the question of whether glucose is a culprit in coronary risk or whether it simply “runs in bad company.”
EARLIER CLINICAL TRIALS SUGGEST INTENSIVE TREATMENT RAISES RISK
Even though it has been widely believed that intensive glucose-lowering would reduce cardiovascular risk in type 2 diabetes, there have been hints in previous studies that some intensive-treatment regimens might increase risk.
Two large randomized clinical trials and one small one (discussed below) addressed whether glucose control would reduce the risk of atherosclerotic vascular disease events. In each of them, an increased risk of cardiovascular events and possibly of death was seen in at least one intensively treated group.
In the following discussion, I have calculated all of the death rates as the number of deaths per 1,000 patients per year, based on published study results. In this way, we can compare the rates in the various studies (including ACCORD), regardless of the trial duration.
The university group Diabetes Program: Controvery about tolbutamide therapy
The University Group Diabetes Program (UGDP)11–16 included about 1,000 participants randomized to five treatments: tolbutamide (Orinase, a sulfonylurea), insulin in a fixed dose based on body weight, insulin in adjusted doses based on fasting glucose levels, placebo, and (later) phenformin.
In the 1970s, when the UGDP was carried out, randomized clinical trials were uncommon. Like other trials from that era, the UGDP was underpowered by today’s standards and did not have a data safety and monitoring board.
Rates of cardiovascular events and deaths (per 1,000 patient-years):
- 25 (tolbutamide group)
- 12 (placebo group).
The two insulin groups did not differ from the placebo group in their rates of cardiovascular events or death.15 The tolbutamide arm was stopped, and the ensuing controversy about how to interpret the trial results lasted for more than a decade. It also resulted in a black-box warning for tolbutamide and all subsequent sulfonylureas.
