Does the FDA’s recommendation regarding CV risk potential in type 2 diabetes drugs seem reasonable?

It is an extremely important move to ensure safety.

It is extremely important to make sure that new medications for type 2 diabetes do not increase the risk of CV events. This has been found with several new medications, as well as some medications already in use.

The problem is that many of the studies that look at the risk for CV events take years to accomplish, so the time frame for completion of these studies may be much longer than the time frame for the evaluation of the general safety of the medications and their effectiveness in treating diabetes. Also, the risk of CV events may occur primarily in subpopulations rather than the general population of people with type 2 diabetes. We are concerned that the requirement that any possible CV risk be ruled out might impair the ability of new, effective drugs for diabetes coming to market.

James L. Rosenzweig

The FDA should consider a two-step process — first evaluate new diabetes medications for clinical effectiveness and safety, and if they meet these criteria, approval of the drugs could be given while longer studies to evaluate CV risk in large populations could be carried out.

The major drugs that lower glucose have been shown to reduce the microvascular complications of diabetes significantly as long as glucose levels have been lowered. This has been shown in numerous studies, and it is assumed is an effect of the lowering of glucose rather than the use of the medications. It has been more difficult to show that improving glycemic control reduces the risk for macrovascular disease (MI and stroke) in prospective randomized studies. Epidemiological studies have shown a significant association between good glucose control and reduced risk of macrovascular disease.

One recent study (ACCORD) showed that if you attempt very tight glucose control in patients already at risk for CVD, that there may be increased risk of mortality in those with very tight control compared with those with just “good” control. Other studies have not confirmed this, but they were not performed in exactly the same way, so the area is a subject of debate. There may be a subset of patients with diabetes, probably in the older population, in which the risk/benefit ratio of very tight glucose control may not be favorable.

The benefits are that the FDA is becoming increasingly aware of the long-term CV implications of the use of these medications and is taking steps to look carefully at CV risk. The negative is that it is possible that, in the future, it might take longer for important medications to get FDA approval.

James L. Rosenzweig, MD, is Director of Diabetes Services at Boston Medical Center and is an Associate Professor of Medicine at the Boston University School of Medicine.

It will delay the options to treat diabetes.

It’s a cautious step by FDA for patient safety. Unfortunately, CVD is the cause of death in more than 85% of people with diabetes.

This prerequisite from FDA, if enforced, will result in delay in availability of new agents that can be used to manage diabetics, as it will take much longer clinical trials to provide complete CV safety of any agent and to decipher and separate the negative impact of the agent in a disease state that preferentially attacks CV system itself. Suffice to say that it’s a daunting task for drug companies.

Intekhab Ahmed

As mentioned above, it is hard to separate the negative impact of the drug from the natural history of the diabetes since biochemical changes in uncontrolled diabetes are responsible for deterioration in CV system. Metformin has shown to be somewhat effective in ameliorating CVD in long-term follow up in UKPDS, though not to a statistically significant extent.

Current understanding of pathophysiology of diabetes strongly suggests that abnormal biochemical milieu like abnormal lipids, BP, and insulin resistance in people with diabetes is responsible for increased CV morbidity and mortality.

It’s a double-edge sword; on one end it places more responsibility on pharmaceutical companies to be more thorough in their discovery and delivery of drugs in the market, and at the same time it will delay availability of new compounds that can be beneficial to the patients.

This will definitely delay the options available to treat diabetes. If drug companies take too much time to investigate their compounds, endocrinologists will be left with old frustrating options.

Intekhab Ahmed, MD, FACP, FACE, is an Associate Professor of Clinical Medicine in the Division of Endocrinology, Diabetes & Metabolic Diseases at Jefferson Medical College of Thomas Jefferson University.