Positive Interim Results for New T2 Treatment Protocol

In his 2008 ADA Banting Award lecture, Ralph DeFronzo challenged the established models of diabetes treatment and proposed a radical departure. Instead of the usual stepwise treatment, starting with a small dose of a single drug and then escalating as the patient lost blood sugar control, why not start with the most effective combination. The hypothesis was that tight blood sugar control would enable the treatment to be durable. The ADA took DeFronzo up on his challenge and funded a clinical trial of his protocol and the first results were presented at the EASD. As reported in InternalMedicineNews:

Starting a triple-drug regimen of metformin, exenatide, and pioglitazone at the onset of type 2 diabetes decreased 2-year treatment failure rates by 84%, compared with a conventional, stepwise treatment program.

After 2 years, patients taking the combination treatment showed significantly lower hemoglobin A1c levels than those who had graduated treatment – a mean of 5.9% vs. 6.6%, Dr. Ralph A. DeFronzo said at the annual meeting of the European Association for the Study of Diabetes.

I think this is an important result. It could significantly change the way that we as T2 patients are treated and greatly improve the progression of our condition. What are your thoughts?

Those results are striking. The protocol also calls for and A1c of 6.5% which is ambitious. A mean of 5.9% is crazy good, especially considering 17% of the treatment group did not achieve 6.5%. Those who are doing well must be doing really well A1c-wise.

I'd be concerned about side effects of this intensive treatment though. I'm not familiar with the drugs used but from reading this board I'm given the impression that side-effects can be significant.

It would be interesting to see a second treatment group that either incoporates insulin into the drug therapy, or uses insulin instead of the triple drug therapy.

Actually, insulin isn't disregarded from DeFronzo's protocol. He argues that a newly diagnosed T2 should immediately start on the triple regime (metformin, TZD and GLP-1) and that tight control from the beginning gives you the best change of a reducing the progression of diabetes. Then when the triple regime fails, you just move to insulin.

Most medical professionals believe a T2's blood sugar numbers inevitably deteriorate over time. This study seems to show that more ambitious goals leading to better control lead to a better prognosis. Lowering carbs can sometimes reduce the number of drugs prescribed and still achieve a similar result.

Brian - Thanks for the update.

What little I know about this protocol, I've read here and diabetes news aggregator sites. It's always good to see the status quo challenged and studies affirm their assertions. In the end, closer-to-normal BGs are better than higher ones. Sometimes it takes new and radical thinking to shake things up.

I think it sounds like a good plan and then move to insulin if it doesn't work. I also agree with badmoon that low carbs should be added in too. I'm going to send this link to my friend whose brother was newly diagnosed type 2. I'm not sure what program he is following but I know he's not on insulin yet.

I support anything involving Gila Monster venom! I'd like to have some just to say I had Gila Monster venom...

That is an important point. In his work, DeFronzo has been really clear that a central hypothesis is that normalized blood sugars preserve beta cells. He did a bunch of work to provide evidence of this and if you read his writings and his Banting Award paper he talks very specifically about this glucotoxicity. For years Bernstein has argued that normalized blood sugars could reduce beta cell destruction in both T1 and T2 diabetes.

Actually, I believe it is Gila Monster "spit." And Gila Monster spit has lots of bad stuff in it, including:

Four potentially lethal toxins have been isolated from the Gila monster's venom, including horridum venom, which causes hemorrhage in internal organs and exophthalmos (bulging of the eyes)[1], and helothermine, which causes lethargy, partial paralysis of the limbs, and hypothermia in rats.

I'm pretty sure they don't put that stuff in Byetta.

Aggressive treatment of any kind is going to be beneficial to A1C, but these medicines have strong side effects as well (both short and long term), and part of the reason for a slow progression is to figure out the SE of each drug. I'd also like to see the number of low events and how much time the doctors spent with the 2 groups of patients.

Personally, I'd like to see a 3rd group....
T1 screening, followed by a low carb diet (less than 100g) with metformin, and then adding insulin if the diet, met and maybe exercise don't work. IMHO, getting a sub 6 A1C shouldn't be that hard for a T2. Even if you feel that more carbs are necessary, taking these 3 meds is probably a lot worse. I'd be cheaper, simpler, and probably have much better results.

In practice, there's a strong bias towards getting T2 diabetics on a bunch of meds and if the meds aren't balanced perfectly, BG can be very chaotic and the game is lost. This is especially if the person is really a T1 because then the doctors will keep them on 2-3 meds and add insulin to help.

This is wonderful news! But I have to say.....

.....is anyone here surprised? :-)

My impression is that failure to get that blood glucose early results in higher
blood glucose in blood system. My read as the islets sit in higher glucose levels they can reduce insulin output over time and finally drop very low. Hence the deterioration prognosis over time.

Some new research out there suggests getting the blood glucose back down to more normal can be helpful getting the islets back on the job - recover. The more aggressive - bariatric surgery/600 calorie diets; the faster the islets come back on the job.

I have to say, looking back on my own T2 progression on the current guidelines, that this approach is breath taking. I was never really controlled and I felt I was suffering one defeat after another when each step along the way wasn't enough. It might have been nice to have a win in the beginning, It might have made a difference in how I perceived my T2.

I always felt helpless until I reached my current stage of treatment where insulin finally brought my T2 under control. Its nice to be a winner it has made me work even harder.

I always wonder why they start with lifestyle control. When I was diagnosed I spent a month or more with no drugs. I beat myself up. Starved. And due to extreme exercise damaged my rotator cuffs which recently came back and haunted me and now always hurts. When I returned to the dr. and CDE I was told that no one believed I could be diet controlled to begin with due to my young age and high activity level. I think I was at 300+ before all these efforts and managed to drop down to 290 with the changes, mostly by cutting out some of the whole grain carbs and fruit since I pretty much ate healthy stuff.

For me, met, diet and exercise did work ok for about 10 years. The next 5 years it didn't. Last year I ended up on Amaryl which helps a lot but I still am running around 140 fasting. The rest of the day I'm fairly good if I really watch what I eat and make sure I exercise.

My insulin production is at the bottom of normal. I worry the Amaryl is going to make my beta cells die off even faster but since I'm T2 (I've had 2 drs. tell me they thought I was LADA with a very slow onset but due to insurance and now a change in drs. no one is letting me be tested). I think my life would be greatly improved if they would have put me on insulin years ago. I'm 48 and have mild neuropathy.