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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.

United Kingdom Prospective Diabetes Study: Method of glucose-lowering an issue

The United Kingdom Prospective Diabetes Study (UKPDS)17–27 was launched in 1977. A cohort of 5,102 patients (mean age 54 years) with newly diagnosed type 2 diabetes mellitus followed a “prudent diet” for the first 3 to 4 months. Then, if their fasting glucose levels were in the range of 6.1 to 15 mmol/L (110–270 mg/dL), they were randomized to receive various treatments.

Patients who were not obese were randomized to receive either intensive treatment or conventional treatment. The intensive-treatment group received either insulin or a sulfonylurea (chlorpropamide [Diabinese], glibenclamide, or glipizide [Glucotrol]); the conventional-treatment group received diet therapy. The sulfonylurea arm was included partly to address the UGDP results.

Patients who were obese were randomized to receive one of three treatments: intensive treatment (with the agents listed above), conventional treatment, or metformin (Fortamet, Glucophage).

The mean in-trial hemoglobin A1c level in the intensive-treatment group was 7.0%, compared with 7.9% in the conventional-treatment group.

After a mean follow-up of more than 10 years, the incidence of myocardial infarction was 16% lower in the intensive-treatment group, but the difference was not statistically significant (P = .052).

Rates of death from all causes among nonobese subjects (per 1,000 patient-years):

  • 18.2–20.5 (intensive-treatment group)
  • 19.9 (conventional-treatment group).

In the obese patients who received metformin, the incidence of myocardial infarction was lower than in the conventional-treatment group but not the intensive-treatment group.

Rates of death among obese patients (per 1,000 patient-years):

  • 13.5 (metformin group)
  • 18.9 (intensive-treatment group)
  • 20.6 (conventional-treatment group).

However, a small subset (n = 587) of the original group assigned to sulfonylurea therapy whose glycemic control deteriorated during the trial were rerandomized to continue to receive a sulfonylurea alone or to have metformin added. There was a statistically significantly higher rate of cardiovascular events and a nonsignificantly higher rate of total mortality in the metformin-plus-sulfonylurea group (30.3 per 1,000 patient-years) than in the sulfonylurea-only group (19.1 per 1,000 patient-years).

These data suggested that the way glucose-lowering was achieved might be as important as the glucose levels actually achieved. However, no definite conclusions could be drawn.

In an editorial on the UKPDS, Nathan26 made a comment that may have been prescient in terms of the ACCORD trial: “Professional organizations will now scramble to decide how to translate the UKPDS results … Whether the UKPDS firmly establishes the choice of any one therapy…or any combination of therapies for the long-term treatment of type 2 diabetes is more questionable.”26

Veterans Administration feasibility study

A Veterans Administration feasibility study28,29 included 153 men (mean age 60) with type 2 diabetes (mean duration 7.8 years) who received either conventional therapy (a single daily dose of insulin) or intensive therapy (multiple doses of insulin plus a sulfonylurea). Over a mean of 27 months, the intensive-therapy group achieved a hemoglobin A1c level that was 2 percentage points lower than in the conventional-therapy group.

At 2.25 years of follow-up, cardiovascular events had occurred in 24 (24%) of the intensive-therapy group and in 16 (20%) of the standard-therapy group (P = .10).

Rates of death from all causes (per 1,000 patient-years):

  • 28.9 (intensive-treatment group)
  • 17.5 (conventional-treatment group).

ACCORD TRIAL DESIGN

ACCORD had a double two-by-two factorial design: all of the more than 10,000 patients were randomly assigned to undergo either intensive or standard glucose-lowering therapy; in addition, approximately half were randomly assigned to receive either aggressive or standard antihypertensive therapy, and the other half were randomly assigned to receive one of two lipid-lowering regimens (Table 1).

The primary outcome measured was the combined incidence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Secondary outcomes included death from any cause. The study is also evaluating the effect of intensive treatment on microvascular disease, hypoglycemia, cognition, quality of life, and cost-effectiveness.

The ACCORD study was designed to have 89% power to detect a 15% treatment effect of intensive glycemic control compared with standard glycemic control for the primary end point.

ACCORD RESULTS

Participants in ACCORD were between the ages of 40 and 82 at randomization and were generally at high risk of coronary heart disease on the basis of having multiple risk factors or a prior event. Table 2 summarizes their baseline characteristics.3

From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545-2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.
Figure 1. Median hemoglobin A1c levels at each study visit in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Bars denote interquartile ranges.
At 1 year, the median hemoglobin A1c value had fallen from 8.1% at baseline to 6.4% in the intensive-treatment group and to 7.5% in the standard-treatment group, and these values remained stable throughout the rest of the trial (Figure 1).1
From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545-2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.
Figure 2. Kaplan-Meier curves for the combined primary outcome (the first occurrence of nonfatal myocardial infarction or nonfatal stroke or death from cardiovascular causes) in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
At a median of 3.4 years, the primary outcome (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) had occurred in 6.9% of the intensive-therapy group compared with 7.2% of the standard-therapy group (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.78–1.04, P = .16) (Figure 2).1 The difference was primarily due to a lower rate of nonfatal myocardial infarction in the intensive-therapy group (n = 186, 3.6%) than in the standard-therapy group (n = 235, 4.6%; HR 0.76, 95% CI 0.62–0.92, P = .004).1
From Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559. Copyright 2008, Massachusetts Medical Society. All rights reserved.
Figure 3. Kaplan-Meier curves for death from any cause in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
However, on February 6, 2008, the ACCORD trial announced that 257 (5%) of the patients in the intensive-treatment group had died, compared with 203 (4%) of the standard-treatment group, a 20% difference (P = .04) (Figure 3).1

Rates of death from any cause (per 1,000 patient-years):

  • 14 (intensive-treatment group)
  • 11 (standard-treatment group).

Although this difference was relatively small by some standards, it was statistically significant (P = .04).1 The number needed to harm was 333 patients for 1 excess death. The difference was attributable to cardiovascular deaths (Table 3).1

In the analyses available at the time that this study arm closed, the excess mortality was not attributable to any particular treatment regimen. In particular, rosiglitazone (Avandia) use did not contribute to the excess mortality. (Of note, 91.2% of the intensive-treatment group and 57.5% of the conventional-treatment group had been treated with rosiglitazone, with more than 19,000 patient-years of rosiglitazone exposure). The excess mortality was also not attributable to hypoglycemia immediately proximate to the death.

The ACCORD trial’s data safety and monitoring board recommended that this arm of the study be discontinued for safety reasons, and this recommendation was accepted by the NHLBI project office. All participants were notified by letter before the trial results were announced publicly, and all intensive-therapy group participants are now being treated by the protocol used in the standard-therapy group.1

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