Type 2 diabetes is a progressive disease with worsening beta cell function over time. Traditional treatment of type 2 diabetes begins with oral medications, including metformin, sulfonylureas, or DPP-4 inhibitors and then progresses to GLP-1 agonists and/or insulin injections. Dr. Mariela Glandt, an endocrinologist and director of the Diabetes Medical Center in Tel Aviv, however, uses a short course of intensive insulin therapy in order to “reset” beta cells and help them return to an earlier and more manageable stage of the disease.
Beta cell function declines in response to multiple factors in type 2 diabetes, and insulin therapy has been shown to counteract several of these. For example, treatment with insulin can reduce glucotoxicity – the toxic effects of excess sugar in the blood, lipotoxicity (due to chronically elevated free fatty acids), inflammation, and resistance to incretins.
Studies have shown the effectiveness of short-term intensive insulin therapy (IIT) early in the presentation of type 2 diabetes. Dr. Glandt is applying this same concept to treat diabetes years after the original diagnosis. In her private practice she has brought over 80 patients with complicated diabetes to a place where their diabetes is much easier to manage, and they have near normal A1c’s.
When did you start treating patients with intensive insulin therapy?
It all started when a patient with a 10-year history of diabetes and an A1c of 14% came into my office. His previous doctor had prescribed Janumet, a combination pill of metformin and sitagliptin, a few months prior to the visit, but still there was no improvement, and he was exhausted and hopeless. I suggested he stay on the medication he was taking, but told him that in addition to his current medication, from now on he should behave as if he has type 1 diabetes, meaning he would take insulin with everything he ate (including snacks).
I started treating my new patient with low doses of insulin and made the corrections slowly because I knew that if l lowered his blood sugar too fast he would feel bad, as if he were hypoglycemic, although he really wasn’t. I told him to come to the clinic every week, and we slowly fine-tuned his insulin regimen. At first I increased and increased the insulin doses, then after a while of his blood sugar levels being near normal, he started to need less and less insulin. After 6 weeks, I was able to peel off the insulin entirely and he ended right back on his original medication, Janumet. Now, more than two years later, he is still on Janumet with A1c of 6.9%.
Since then I’ve treated dozens of patients this way and I am shocked by the successful results. On average my patients have been diabetic for 10 years and on average their A1c is 9.8% at the beginning of treatment. After 6 months the average A1c is 6.9%
Most patients who have A1c of 14% are placed on insulin. What’s different about your treatment?
I think the key point is that the insulin has to be taken in such a way as to really bring the blood sugar close to normal levels. Most patients like this would be started on insulin and would probably be kept on it for the rest of their lives. It is the fact that my patients take insulin like a patient who has well treated type 1 that allows the pancreas to start working, as I see by the fact that they don’t need insulin anymore and still their sugars are well-controlled
What is the mechanism behind this?
A few studies (see footnote 1) conducted on patients close to the time of diabetes diagnosis show that when insulin is given this way for a few weeks, the patients can revert to a state of no-diabetes for one to two years. It is believed to be due to the fact that the beta cells improve their function when they are no longer smothered in sugar. High glucose levels are toxic to cells (glucotoxicity), which means that the cells are stunned and cannot secrete insulin appropriately. Generally, these cells are not dead and can go back to working if given the opportunity. As I often say, “give beta cells a chance.”
Since these patients have had diabetes for many years, what are your expectations after the intensive insulin therapy?
Some beta cell deterioration is reversible and some is not. It seems to depend on how long the patient was exposed to hyperglycemia and the degree of hyperglycemia.
Those who are recently diagnosed are able to come off medications for one to two years and remain in good control. Those who have had diabetes for ten years (which is the average I see in my clinic) are able to significantly improve their insulin secretion, but must continue to take simpler medications, that don’t require frequent checking of blood sugar levels because they don’t lead to hypoglycemia.
So which medications are used after the intensive treatment is over?
Unless there is a contraindication most patients are kept on metformin- a very safe and well known drug. In addition, GLP-1 agonists such as liraglutide seem to be very effective – they help with both weight maintenance and keep blood glucose levels in the range of normal without putting the patient at risk for hypoglycemia. The downside of GLP-1 agonists is that they are expensive.
Many patients come to me already on a GLP-1 agonist, but because their glucose levels are high, the GLP-1 agonist is not working. However, as soon as the glucotoxicity goes away with the insulin treatment, the GLP-1 agonist starts to work and patients even start to complain of the usual side effects as if they had just started taking the medication. I often have to lower the dose of GLP-1 when I start intensive insulin therapy just so patients won’t suddenly get the side effects. There is a paper that shows that when beta cells are exposed to hyperglycemia for a long time they lose the GLP-1 receptors. When they are re-exposed to normal sugars then the beta cells regain the GLP-1 receptors. This helps to explain the phenomenon I often see in clinical practice. Suddenly, a medication like liraglutide, which was described to me by the patient as “it did nothing for me” is now very effective.
Are you really able to stop the insulin on all patients?
Certainly not on all patients, but in those who I don’t manage to take off the insulin entirely, they often remain only on a low dose of long acting insulin. Eating a low carb diet and doing some kind of physical activity, of course, significantly improves the chances of coming off insulin, even if the patient has been a diabetic 20 years.
It seems like you have to bring the patients’ blood sugar levels quite close to normal for this to work. In these patients who on average have had diabetes for 10 years, are you concerned about the data from studies like the ACCORD trial which showed that bringing glucose to near-normal levels in patients with long history of diabetes increased cardiovascular risk.
[The goal of ACCORD (the part that checked the impact of glycemia) was to determine whether cardiovascular disease event rates could be reduced by intensively treating glucose levels. There were two arms of the study – one aiming for A1C <6 an the other 7–7.9%]
It is, of course, something I have given a lot of thought to, but my understanding from trials like the ACCORD trial is that low A1C is unlikely to account for the increased risk of mortality. In fact, rapid reduction of A1C from high levels did not increase risk of death. Participants who were unable to reduce A1C after starting the intensive strategy and continued to have average A1C >7% seemed to be at greater risk than those with average A1C <7% using the same strategy or than those with A1C >7% using a standard strategy.
In my clinic I have always seen glucose levels decrease relatively slowly but surely, with no hypoglycemic events because the insulin is given in a physiological way, and the treatment includes very frequent contact with the doctor, nurse, and dietician.
A recent publication from the ACCORD trial actually showed that the intensive arm (which reached HbA1c levels below 6.5% ) had great glucose control more than one year after therapy is relaxed, which is similar to my findings.
How do you convince patients to take 4 shots a day (at a minimum)?
It’s not so hard because most of these patients are tired of feeling that diabetes is uncontrolled, doing damage, and that they can’t do much about it. The good news is that the plan is to be on insulin for one to two months. Because it is temporary, it’s easier to accept. The interesting part is that many patients actually enjoy the process because insulin becomes a tool that empowers them and gives them back control over their life (even for those on multiple shots a day for years). I achieve this with the help of a glucometer called Insulinx, which has a built in sliding scale and recommends to the patient how much insulin to take according to what I program in it, and the dose is something that I change on a weekly basis. It’s a very helpful tool.
How long does diabetes stay well controlled after they stop the insulin?
We know from the trials (see footnote 1) done in patients with new onset diabetes that the beta cell improvements seen after intensive insulin therapy decline over time. In our practice we’ve seen over the last two years that overall patients are able to stay with A1c under 7%, particularly if they are on GLP-1 agonist. A study by Ravi Retnakaran presented at the America Diabetes Assoication’s Scientific Sessions Conference in Chicago last month showed that liraglutide after a short course of intensive insulin therapy preserved the beta cell function gained after a short course of intensive insulin therapy.
The exception is in cases where patients have other reasons to go off track, for example intermittent illness, such as an asthmatic patient who requires high doses of steroids. In some cases A1c starts to go slightly up and the patients themselves request a “booster” (another short course of intensive insulin therapy).
The ongoing RESET IT trial investigates the effect of administering a short course of intensive insulin therapy every three months –i.e., using insulin as both the initial and maintenance therapy. It will be interesting to see the results of that.
This whole process seems like a lot of work for you and the patients, but the results are so impressive. I assume it’s all worth it.
For me it’s worth it because I see how the patients react. At the beginning it’s tough because of the amount of injections. But as patients gain control over their lives and they feel great because they are no longer tired due to the chronic hyperglycemia, I sometimes have to convince them that it’s time to stop.
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