2009: Year in Review (Continued)

Scientific Studies of Note from 2009

  • New ACCORD data: This is turning out to be one of the most confusing studies in diabetes! You might recall that the ACCORD trial, published in 2008, compared intensive glycemic control (target A1C below 6.0%) versus a conventional target range (A1C of 7.0-7.9%) in people with type 2 diabetes. At the end of the study, which lasted 3.5 years, intensively managed patients had a higher rate of mortality! Headlines screamed, "Tight Glucose Control Kills You!" (We're exaggerating, but the reaction to the study sometimes overshadowed the real importance of tight glucose control in preventing complications.) Everybody was in a race to figure out why. This year at ADA, further data were released that raised even more questions. Despite the fact that patients in the intensively managed group had a higher rate of mortality, in the total population (both intensive and conventional arms) it was found that patients with lower A1Cs had lower rates of mortality – and some speculated that hypoglycemia may have caused higher mortality in the intensively controlled group, not tighter control per se. In addition, people whose A1C did not improve in the first year of the study had a higher rate of mortality. These analyses suggest that some persons with type 2 diabetes can safely achieve A1C levels below 7% using an intensive strategy, whereas certain sub-segments of patients – namely those who have had diabetes a very long duration - may be at risk if they persist in this strategy. If that isn't a positive argument to pursue early, optimized therapy, we don't know what is! If you feel your doctor isn't individualizing your therapy appropriately and you don't feel you are at major risk for severe hypoglycemia, please ask him or her for ideas to help you reach a 7% A1C or less – every patient, in our view, deserves to have an A1C of 7% or less, but at press time, just 50% of patients in the U.S. had reached this. Some physicians read ACCORD and believed that easing up on control was the answer, so if you feel you aren't in the best control you can be, do ask your doctor for a discussion on this matter.

  • Exenatide Once Weekly versus Lantus: Exenatide Once Weekly is in development by three companies – Amylin, Eli Lilly, and Alkermes. It lowers blood glucose in a glycemic-dependent manner (reducing the risk of hypoglycemia) and is injected only once every week. It was submitted to the FDA for approval in May 2009. In the DURATION-3 trial, Exenatide Once Weekly was compared to the long-acting insulin Lantus in patients with type 2 diabetes. Notably, Exenatide Once Weekly showed superior glycemic control after 26 weeks, with an average A1C drop of 1.5% compared to 1.3% for Lantus. The baseline A1C (in other words, the average A1C people started with) in both groups was 8.3%. In addition, there were fewer incidents of hypoglycemia for people taking Exenatide Once Weekly – a key patient benefit. Although the idea of a once-weekly injection that's more effective than insulin sounds highly appealing, there may be drawbacks. First of all, about 15% of patients who take Exenatide Once Weekly will likely experience nausea – though this is significantly lower (by about 40%) than those on Byetta, it will still affect some. Second, in its first generation, the needle gauge used for EOW will likely be 25 gauge – this may be more painful for some patients. I haven't used a 25-gauge needle for anything lately but I did get a flu shot with one recently and have to say I didn't notice the gauge at all – maybe since someone else was doing the shot, but that's the closest comparison I've got. We believe that if there are no safety or convenience issues, this could be the product of the decade.

  • 4-T: The 4-T trial was designed to compare the effectiveness of basal (long-acting), prandial (mealtime), and biphasic (mix) insulin regimens for type 2 patients. Patients were randomized to either basal, prandial, or biphasic insulin. After the first year, the basal group had the poorest control, but the least weight gain and hypoglycemia. A1C in all groups went from around 8.5% to around 7.5%. The groups were targeted to an A1C of 6.5%. After the end of the first year, patients not reaching 6.5% A1C added another type of insulin, so that those originally on basal added prandial, those originally on prandial added basal and those on biphasic added a lunchtime prandial injection. At the end of the trial, 75% of all patients had added a second insulin. At the end of the third year, A1C was 7.1% for the biphasic arm. 6.8% for the prandial arm, and 6.9% for the basal arm. In fact, 43% of the (original) basal group reached an A1C <6.5%, an impressive accomplishment. Patients originally starting on basal had the best glucose control, the best rate of hypoglycemia, and the lowest weight gain. Therefore, the 4-T study group concluded that the best way to give insulin is basal first and then transition to a basal/prandial regimen. From our view, the most important finding was not that basal insulin was the way to start, but that insulin must be used in advancing stages – in other words, starting with insulin is fine, but people with type 2 must review frequently what is working and whether or not they need to advance to more shots per day. Ultimately we think we will start seeing more type 2 patients on pumps and using pens as they seek to optimize treatment.

  • RECORD: In 2008, Dr. Steven Nissen published an analysis of several published studies on rosiglitazone, also known as Avandia. His now very-well known analysis suggested that rosiglitazone might heighten the risk of heart attacks. The assessment gained great attention and in our view has been the cause of Avandia sales dropping from $3 billion in 2006 to $1 billion in 2009. Later, the paper was criticized because, among other reasons, it combined the results of differently designed studies. The results from the RECORD trial that finished this year were long awaited since it was thought that they might give evidence that could bolster or contradict Dr. Nissen's meta-analysis. In RECORD, 4,447 patients were randomized to receive either rosiglitazone or a placebo and were monitored for an average of 3.75 years. RECORD showed no increase in heart attacks in the rosiglitazone group, essentially discrediting Dr. Nissen's analysis. Nonetheless, the damage to rosiglitazone has been done, and RECORD has done little to rescue its market standing.

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Last Modified Date: April 23, 2013

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