Insulin treatment is following Moore’s law. Type 2 Diabetes is Following Parkinson's Law.
A phase 2 trial comparing once weekly insulin injection (icodec) to daily insulin injection (glargine) in type 2 diabetics was published in NEJM this week. Insulin is one of the most difficult treatments for patients to stick with and understand. This often leads to poor compliance and poor control of the disease.
First, insulin is administered via an injection. Although the injection is not very painful it is cumbersome. Ask anyone and they would prefer a pill. The treatment protocol is difficult to understand. Most diabetics require two types of insulin, long-acting daily injections and short acting insulin to cover meals. It requires blood sugar checks prior to administration to avoid overdoses. Patients often skip their protocol due to the inconveniences of daily life, i.e. grabbing a quick bite after grocery shopping, or sitting around a dinner table with family and friends. It’s a burdensome disease.
Innovation in the treatment of type 2 diabetes has been focused on improving convenience and safety. Once weekly insulin injections would be a substantial improvement in this arena. Especially those in a current disease state that do not require mealtime injections.
The trial was a randomized double blind, double dummy, target to treat, active controlled, parallel-group, comparison trial. Eligible patients were type 2 diabetics that were poorly controlled and insulin naive. They were followed for 26 weeks. The primary endpoint was % reduction in Hgb A1c, which is a test we use to track severity of diabetes. The primary safety endpoint was hypoglycemic events.
Let’s break this design down.
Randomized = The participants were randomly assigned to either the experimental or control group.
Double Blind = Investigators and participants were blinded to the group they were allocated to.
Double Dummy = Regardless of which group the participant was assigned they had to do the once weekly injection and a daily injection. They just didn’t know which one was the placebo. Obviously, it would be easy to figure out which group you were assigned if you were just giving yourself the injection once per week.
Treat to Target = They tested the participants frequently to ensure that all participants randomized achieved at least a 0.5% drop in Hgb A1c.
Active controlled = This just means they did not compare the treatment to a placebo. Thank goodness! Can we please stop comparing treatments to placebo when there’s a treatment already available?
Parallel group = This just means the patients didn’t cross over to the other group.
Here are the results.
There were no significant differences between the groups, demonstrating that the randomization strategy was successful. Completion of the protocol was 96% and 94% in the experimental and control group respectively. Mean starting A1c was 8.09% and 7.96% in the experimental and control groups respectively.
The experimental group achieved a mean reduction in A1c to 6.69%. The control group achieved a mean reduction in A1c to 6.87%. This was close to statistically significant, but the confidence interval did cross 0, which is not significant (-.38 - .02). However, the design of this trial was to establish safety, and equivalent efficacy. The goal was not to prove superiority (phase 2).
Moderate to severe hypoglycemia occurred in 16.0% of the weekly insulin participants compared to 9.8% in the daily insulin users.
The authors found that once weekly injections were equivalent to daily injections with a tolerable safety profile. The study checks all the boxes. The design was great. There was little opportunity for bias to be introduced. They had virtually no loss to follow-up. The result was robust and showed that it was just as good. This is the entire point of once daily injections. Reduce burden on the patient to achieve better compliance and therefore control. The only issue was the high percentage of hypoglycemic events. This will be troublesome if not improved upon in the phase 3, or after market research. Novo Nordisk is one of the pioneers of diabetes management and they continue to innovate in this space.
Interestingly, insulin development is following Moore’s law. Moore’s law comes from the semi-conductor industry. As the story goes, Gordon Moore (co-founder of intel) predicted that the number of components per integrated circuit would double each year due to improved performance of processing chips. He made this prediction in 1975 and it continues to hold true today. As a result, we have computers that continue to get smaller and have more power. So small, they fit in your pocket.
The first insulin developed was extracted from pigs. The initial batches were so bad that the purity level of available insulin in 1923 was about 5%. In 1946, NPH insulin was the first long-acting insulin to be commercially available. In 1970, the first analog single molecule insulin, was created substantially improving its purity. This allowed for smaller volume and more precise injections. Insulin glargine, the first long acting once daily insulin, was approved in 2000. Further innovation has led us where we are today. A once weekly, small volume insulin injection for type 2 diabetics.
Parkinson’s law is an old adage that simply states, work will fill the time allotted for it. I find this true for type 2 diabetes, which for most patients is self-inflicted. Technology is advancing and the disease is running to catch up. As technology and treatments appear less burdensome, the fear of developing the disease diminishes. The individual does not bear the entire cost and burden of the disease. It is spread out in cooperative fashion amongst insurance plan participants, and federal program beneficiaries. As treatments become more sophisticated, the complications of the disease are spread on a longer timeline, making them more difficult to recognize. To an outsider the impact of the disease is dampened. However, quality of life diminishes slowly, and the afflicted carry a high disease burden.
It seems that some diseases develop this paradox to innovation. As disease sustaining treatments advance, individuals take greater risks with their health, then the disease expands to close the gap. No progress is made. It’s an arms race. It may be best to not innovate in every situation. The populous should view the disease as significantly burdensome, and debilitating. To be afraid. Just enough fear to avoid the disease at all costs.
This threat is present every day in my clinic. If I am not vigilant with my health, it may be taken from me. There are thousands of diseases out there that are NOT preventable. I’m going to get at least one of them. It’s inevitable. In actuality, I’ll probably end up with several. One will be the death of me. There’s no room for a disease that could have been prevented. For many of my patients it’s too late. I’m left with only injections and pills to sustain them.
Link to the abstract: https://www.nejm.org/doi/full/10.1056/NEJMoa2022474