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Does intensive therapy of type 2 diabetes help or harm? Seeking accord on ACCORD

A clinician and clinical trialist's perspective
Cleveland Clinic Journal of Medicine. 2008 October;75(10):729-737
October 1, 2008 | Cleveland Clinic Journal of Medicine
Byron J. Hoogwerf, MD
Author and Disclosure Information

Byron J. Hoogwerf, MD
Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic; Principal Investigator (Cleveland Clinic Site), Member, Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group

Address: Byron J. Hoogwerf, MD, Department of Endocrinology, Diabetes, and Metabolism, A53, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail hoogweb@ccf.org

The author has disclosed that he has received honoraria for consulting, teaching, or speaking from the Abbott, Amylin, Lilly, Merck, and Takeda Pharmaceuticals North America corporations. As of October 20th Dr. Hoogwerf will assume a position in the Diabetes Group at Eli Lilly, US Affiliate (at the time the manuscript was submitted, reviewed, and revised he was a full-time staff endocrinologist at the Cleveland Clinic).

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.

FEWER DEATHS IN ACCORD THAN IN OTHER STUDIES IN DIABETES

The mortality rates in both arms of ACCORD were much lower than in other observational studies and clinical trials in type 2 diabetes.

The National Health and Nutrition Education Survey (NHANES),30 conducted from 1971 to 1975, included 14,374 people with diabetes between the ages of 25 and 74. Many of them were younger than the ACCORD patients, but two NHANES age-groups overlapped the ACCORD cohort. Rates of death from any cause at 22 years (per 1,000 patient-years):

  • 39.7 (ages 45–64)
  • 89.7 (ages 65–74).

The NHANES cohort would not have been treated as vigorously for coronary risk and other common causes of death.

UGDP, UKPDS. Death rates in the glucose-lowering trials of type 2 diabetes mellitus cited above were typically in the range of 20 deaths per 1,000 patient-years but were as high as 30 deaths per 1,000 patient-years in the UGDP tolbutamide group16 and the UK-PDS sulfonylurea-plus-metformin group.20,22,26

Steno-2.31 Half of 160 patients with type 2 diabetes were randomized to intensive strategies for controlling glucose, lipids, and blood pressure and for taking aspirin and angiotensin-converting enzyme inhibitors and following a healthy lifestyle. The other half received conventional therapy. Even in the intensive-treatment group, the mortality rate at 13 years was higher than in ACCORD. Rates of death from any cause (per 1,000 patient years):

  • 22.5 (intensive-treatment group)
  • 37.6 (conventional-treatment group).

After the ACCORD results were presented, two other trials addressing the question of whether lower hemoglobin A1c would reduce cardiovascular risk in type 2 diabetes have reported their outcomes:

The ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation),32,33 with 11,140 patients, had a target hemoglobin A1c of 6.5% in an intensive-treatment group and 7.3% in a usual-treatment group. The intensive-treatment group showed no difference in the rates of major macrovascular events (HR 0.94, 95% CI 0.84–1.06, P = .32) or all-cause mortality (HR 0.93, 95% CI 0.83–1.06, P = .32). The overall death rate in ADVANCE (about 18 deaths per 1,000 patient-years) was higher than in ACCORD.

The Veterans Administration Diabetes Trial included 1,791 patients.34 Like the ADVANCE trial, it also found no difference in major cardiovascular outcomes (HR 0.868, P = .11) or cardiovascular mortality rates (HR 1.258, P = .36) with intensive therapy vs conventional therapy, ie, achieved hemoglobin A1c levels of 6.9% vs 8.4% (presented at the American Diabetes Association 2008 Scientific Sessions). Hypoglycemia was associated with an increased risk of death in the standard-treatment group.

An analysis suggested that patients with a shorter duration of diabetes may have had cardiovascular benefit from intensive glucose-lowering, while those who had had it longer may have had increased risk associated with the more intensive therapy. The rate of death from all causes appears to have been higher than in ACCORD, but this could not be determined accurately from the presentations.

Comment. Thus, the ACCORD cohort as a whole has had strikingly lower death rates than in these other studies. The fact that all participants had lower glucose levels on therapy than at baseline may possibly contribute to these lower death rates. In addition, all ACCORD participants in the lipid arm received a statin; all participants in the blood pressure arm had their blood pressure lowered to levels below those commonly seen in clinical practice; participants were encouraged to exercise regularly; most participants were given diet instruction; and other healthy behaviors such as aspirin use, regular follow-up with primary care physicians, and recommendations about smoking were encouraged throughout the study. These comprehensive strategies may represent better care and thus result in lower death rates than in other studies.

POSSIBLE EXPLANATIONS FOR THE ACCORD OUTCOMES

The ACCORD trial has already stimulated fierce debate about the reasons for the higher mortality rate in the intensive-treatment group. With longer follow-up, some new risk factors for death may be identified that are not evident in the analyses of the current 460 deaths. What follows are some of my thoughts, with the caveat that they are not confirmed (supported statistically) by any currently available analyses from ACCORD.

It seems unlikely that lower glucose values as reflected by lower hemoglobin A1c values in the intensive-treatment group are an a priori explanation for the observed differences in mortality rates—especially since the mortality rates were lower than in the NHANES and clinical trial data sets cited above. If we assume that a type 1 statistical error (finding a difference where no difference actually exists) does not explain the findings, then at least four reasonable postulates exist:

Hypoglycemia may have some adverse effect, either acutely or from recurrent events that trigger a catecholamine response with associated risk for arrhythmia or increased coronary heart disease risk. However, the investigators analyzed each death to determine whether hypoglycemia was a contributing cause, and they found no statistically significant relationship between hypoglycemia and death in the intensive-treatment group.

Weight gain is common with intensive therapy. Obesity may be associated with greater cytokine production, higher concentrations of clotting factors, higher levels of free fatty acids, and other potential contributors to the risk of coronary heart disease and death. Currently, the ACCORD analyses do not suggest that weight gain explains the higher death rate.

Medications such as rosiglitazone, sulfonylureas, and the combination of a sulfonylurea plus metformin have been previously associated with increased death rates in some observational and intervention trials. These studies had some serious methodologic limitations (eg, absence of risk adjustment, events not adjudicated, small study cohorts, wide variation in study cohort characteristics) and small numbers of events.11–13,16,26,35 ACCORD analyses have not shown that any single glucose-lowering agent—including rosiglitazone—or combination of agents explains the death rates.

The stress of maintaining glycemic control has been speculated to have in some way contributed to an increased risk. To achieve intensive control, patients had to have frequent contact with their health care providers, they were often told that their hemoglobin A1c values were “too high” even when they were well below those in the American Diabetes Association guidelines, and they had to follow complex glucose-lowering regimens.

Semiquantitative measures of overall attitudes about health exist (eg, the “Feeling Thermometer” scale), but stress was not measured quantitatively in the ACCORD trial.

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