Intensive therapy of type 2 diabetes (ACCORD trial)

To the Editor: I read with great interest Dr. Byron Hoogwerf’s summary¹ of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial² in your October issue.

I am curious as to your opinion, though. I previously e-mailed two other ACCORD investigators to ask if they planned to look at which subgroups were responsible for the higher death rate in the intensive-therapy group. They cannot get this data until after the lipid portion is unblinded next year.

The early release of data and discontinuation of one ACCORD arm is of concern but the data may shed light on the failure of previous trials. Muraglitazar was a failed dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist; it had outstanding effects on surrogate markers but was harmful regarding total mortality.³ The same outcomes were seen in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: lower cardiovascular morbidity rate but higher total mortality rate,⁴ prompting an exchange between Dr. Steven Nissen and me in JAMA in 2006.^5,6

I think it would be prudent to evaluate the total mortality rate as well as cardiovascular morbidity in the study population receiving thiazolidinediones alone, fibric acid alone, both together, or neither. The group of patients most likely to receive both agents (those who are obese, with metabolic syndrome or diabetes) is a very large population. If the data analysis confirms that dual PPAR inhibition raises total mortality rates, that information should be made public as soon as it is available. It may be prudent to review those data before official publication in 2009.

To the Editor: I read with great interest Dr. Byron Hoogwerf’s summary¹ of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial² in your October issue.

I am curious as to your opinion, though. I previously e-mailed two other ACCORD investigators to ask if they planned to look at which subgroups were responsible for the higher death rate in the intensive-therapy group. They cannot get this data until after the lipid portion is unblinded next year.

The early release of data and discontinuation of one ACCORD arm is of concern but the data may shed light on the failure of previous trials. Muraglitazar was a failed dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist; it had outstanding effects on surrogate markers but was harmful regarding total mortality.³ The same outcomes were seen in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: lower cardiovascular morbidity rate but higher total mortality rate,⁴ prompting an exchange between Dr. Steven Nissen and me in JAMA in 2006.^5,6

I think it would be prudent to evaluate the total mortality rate as well as cardiovascular morbidity in the study population receiving thiazolidinediones alone, fibric acid alone, both together, or neither. The group of patients most likely to receive both agents (those who are obese, with metabolic syndrome or diabetes) is a very large population. If the data analysis confirms that dual PPAR inhibition raises total mortality rates, that information should be made public as soon as it is available. It may be prudent to review those data before official publication in 2009.

To the Editor: I read with great interest Dr. Byron Hoogwerf’s summary¹ of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial² in your October issue.

I am curious as to your opinion, though. I previously e-mailed two other ACCORD investigators to ask if they planned to look at which subgroups were responsible for the higher death rate in the intensive-therapy group. They cannot get this data until after the lipid portion is unblinded next year.

The early release of data and discontinuation of one ACCORD arm is of concern but the data may shed light on the failure of previous trials. Muraglitazar was a failed dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist; it had outstanding effects on surrogate markers but was harmful regarding total mortality.³ The same outcomes were seen in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: lower cardiovascular morbidity rate but higher total mortality rate,⁴ prompting an exchange between Dr. Steven Nissen and me in JAMA in 2006.^5,6

I think it would be prudent to evaluate the total mortality rate as well as cardiovascular morbidity in the study population receiving thiazolidinediones alone, fibric acid alone, both together, or neither. The group of patients most likely to receive both agents (those who are obese, with metabolic syndrome or diabetes) is a very large population. If the data analysis confirms that dual PPAR inhibition raises total mortality rates, that information should be made public as soon as it is available. It may be prudent to review those data before official publication in 2009.