What the 4-T study really means!

What the 4-T study really means!

This morning the New England Journal of Medicine released online an article entitled “Addition of Biphasic, Prandial or Basal Insulin to Oral Therapy in Type 2 Diabetes” and an editorial “Intention to Treat – Initiating Insulin and the 4-T Study.”

With the Avandia controversy fresh on everyone’s mind, insulin companies are making the most of this opportunity to show the benefits of insulin therapy in the huge type 2 patient population. Not to be outdone Lilly (NYSE:LLY) has decided to help their partner Amylin (NASDAQ:AMLN) by initiating a major direct to consumer advertising campaign for Byetta. As Diabetic Investor pointed out in an email alert earlier this week Sanofi-Aventis (NYSE;SNY) is running full page ads encouraging type 2 patients and their physicians to consider insulin therapy. Sanofi makes the world’s number one selling insulin Lantus.

Given this environment it’s interesting to note what this study concluded; A single analogue-insulin formulation added to metformin and sulfonylurea resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but were associated with greater risks of hypoglycemia and weight gain. Note the study was sponsored by Novo Nordisk (NYSE:NVO).

The study took 708 patients and divided them into three groups – biphasic insulin aspart (NovoMix 30) twice daily, prandial insulin (Novo Rapid) three times a day and once daily basal insulin detemir (Levemir)- all patients continued to take their oral medications metformin and sulfonylurea. Besides the rather lackluster conclusion there were other interesting tidbits:

1. 1. Of the 936 patients screened for the study only 9 declined to participate and only 4 of those 9 were unwilling to inject insulin – so much for the argument that patients don’t use insulin because their afraid of injections. The study states, “The addition of insulin, despite more frequent injections in the biphasic group and the prandial group, did not affect the assessed quality of life of patients in our study, as reported in previous short-term studies.”

2. 2. According to the study, “Glucose lowering was achieved at the expense of weight gain and an increased risk of hypoglycemia, particularly with the biphasic and prandial regimens. Prandial insulin lowered glycated hemoglobin to the same extent as biphasic insulin but with twice the number of episodes of hypoglycemia and an increase in weight gain of 21%.” This in a nutshell is why physicians, in particular primary care physicians, don’t prescribe insulin for their type 2 patients failing oral therapies. It is also the reason why Byetta is gaining acceptance with these same physicians.

In the editorial that accompanied the study stated “Why did relatively few patients achieve the target level of glycated hemoglobin in the first year of the 4-T study? Though the glycated hemoglobin level and other glucose targets are noted, the titration algorithm used in the study is not provided in detail. It is possible that part of the failure to reach the goal was that the algorithm was insufficiently proactive or was insufficiently implemented, possibly resulting from the diversity of the 58 centers. The investigators did not appear to have a standardized approach to educating and supporting the patients and helping them maintain behavioral changes. Another possibility is that the rate of hypoglycemia in patients receiving prandial and biphasic insulins (with a respective median of eight and four symptomatic hypoglycemic events per patient per year with a glucose level of <56 mg per deciliter) constrained attempts to advance the insulin dose. In addition, previous clinical trials have indicated that the continuing administration of sulfonylureas as insulin is added, as was done in the study by Holman et al., exposes patients to additional hypoglycemic risk without providing additional benefit.” What this statement really says is that prescribing insulin therapy without also providing patient education is a waste of time. Insulin therapy is complex, there are multiple factors that lead to success or failure. Although the results of the study we’re less than impressive, Diabetic Investor sees this more towards how the study was designed and conducted rather than an indictment of using insulin with type 2 patients. With a properly educated patient the use of insulin is safe and effective. Given the sad state of patient education it is unlikely physicians will readily adopt insulin therapy for their type 2 patients who are failing on orals alone. However, the poor quality of patient education plays directly into the hands of Byetta, Liraglutide and the long-acting once a week version of Byetta, Byetta LAR. All three are injected, Byetta twice daily, Liraglutide once a day and once a week for Byetta LAR. All three have proven to be effective at controlling diabetes. The primary adverse event associated with all three, nausea. On the flip side, hypoglycemia is not associated with these compounds. For Byetta and Byetta LAR patients experience progressive weight loss, patients on Liraglutide experience some weight loss although not as dramatic as what’s been seen with Byetta. While Amylin the makers of Byetta or Novo Nordisk the makers of Liraglutide would not publicly state that patients should not check their glucose levels, the fact is there is no need for patients to check their levels prior to taking these medications. Unlike insulin, Byetta, Byetta LAR and Liraglutide are fixed dosed compounds. This a huge advantage when it comes to educating the patient. The bottom line here is insulin requires a fair amount of patient education, while Byetta, Byetta LAR and Liraglutide require only a minimal amount of education. Given all the other positives associated with these drugs, Diabetic Investor sees Amylin and Novo in the catbirds seat. David Kliff Publisher Diabetic Investor www.diabeticinvestor.com www.davesrunfordiabetes.blogspot.com 847-634-4777 800-783-3712 847-634-4646 fax 224-715-3761 mobile