Results from a very interesting and important study were published in this week’s New England Journal of Medicine. The study was entitled “Glucose Control and Vascular Complications in Veterans with type 2 Diabetes,” and written by W. Duckworth and colleagues, members of the Veterans Affairs Diabetes Trial (VADT).
The purpose and design of the study
The primary goal of the study was to determine if intensive treatment of diabetes decreased risks of developing major cardiovascular outcomes defined as a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary artery disease, and amputation for ischemic gangrene. Development/progression of microvascular complications was also monitored.
The study population consisted of 1791 military veterans who had a history of suboptimal response to therapy for type 2 diabetes. At onset, the average duration of diagnosed diabetes was 11.5 years and 40% of the patients had already had a major cardiovascular event. Patients were randomly assigned to either an intensive-therapy (IT) group (IT) or a standard-therapy (ST) group with an operational goal of achieving, on average, a 1.5% reduction in HbA1c in the IT group.
The treatment regimens consisted of 2 oral agents, metformin and rosiglitazone for both IT and ST patients with BMIs 27 or more, and glimepiride and rosiglitazone for those with BMIs less than 27;in the IT patients, maximal doses of the medications were given but only 50% of the maximum in the ST patients. Insulin was used as needed throughout the study in those IT patients with HbA1cs 6% or greater and in ST patients with HbA1cs less than 9% (I confess that I didn’t understand the rationale for their treatment protocol and it was not clearly addressed anywhere in the report). Investigators were free to use any medications they wished throughout the study with the understanding that the goal was to lower HbA1c levels in the IT patients
Study patients were enrolled between December 2000 and May 2003 and followed until May 2008; follow-up was for a maximum of 7.5 years and a minimum of 5 years. Mean Hb1c at baseline was9.4%. Mean HbA1c in the IT and ST groups stabilized after 6 months at 8.4% in the ST group and 6.9% in the IT group. The results showed more or less no differences between the treatment groups for any of the outcomes, cardiovascular or microvascular; sudden cardiovascular deaths were about threefold increased in the IT group but rates of death from cardiovascular causes were similar in the two treatment groups.
What do these results mean?
At first glance, these results are rather depressing; they seem to be telling us that improving risk factors for diabetes complications in paients with type 2 diabetes is of no benefit. I would not be so quick to jump to such a conclusion. First, cardiovascular risk factors were controlled similarly in both treatment groups- too bad there wasn’t a third treatment group where these risk factors were not controlled. Second, the ST and IT groups both showed clinically significant decreases in HbA1c levels, the IT group from 9.4 to 6.9 and the ST group from 9.4 to 8.4. So, were the decreases in outcome risks in the ST group large enough to mask any additional benefit from the lower HbA1cs in the IT group; in essence, what would the results have been if the ST group mean HbA1c had remained at 9.4%?
It is also important to consider the fact that as a group, the study population had longstanding diabetes with poor glycemic control as well as a high prevelance of cardiovascular risk factors (and actual cardiovascular disease). Should one expect things to “turn around” after only about 5.5 years follow-up on average? Finally, I hesitate to mention that both study groups were being treated with rosiglitazone, a drug well known to increase cardiovascular disease, particularly congestive heart failure.
The bottom line
So, as I mentioned earlier, this is an important study BUT I would not jump to unwarranted conclusions given the flaws (Maybe more peculiarities than flaws) of the study design, particularly the fact that the HbA1c level fell appreciably in the ST group. I do not see any reason why a patient with diabetes mellitus, type 1 or 2 shouldn’t strive to improve all known risk factors for diabetes complications while also working hard to minimize the attendant risks, such as increased risks of hypoglycemia. I am looking forward to see how the “experts” deal with this study.
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