A 6-month study examining the effects of hepatic-directed prandial insulin in patients with type 1 diabetes mellitus was presented at ADA 2019.
A recent study has found that hepatic-directed insulin is non-inferior to insulin lispro and its liver-targeted component potentiates insulin effect in type 1 diabetes mellitus patients.
Investigators presented the results of the 6-month study at the American Diabetes Association (ADA) 2019 Scientific Sessions in San Francisco, CA.
The multicenter, randomized, double-blind trial included 176 participants that were randomized 2:1 to receive hepatic directed-insulin lispro (HDV-L) or insulin lispro (LIS). Investigators noted that the primary objective of the study was to evaluate HDV-L A1C non-inferiority, according to a prespecified margin of 0.4%.
Mean A1C change to week 26 was -0.09% in the HDV-L group and -0.16% in the LIS group. Further analyses showed that HDV-L treated subjects with A1C of 8.5% or greater reported less “severe” hypoglycemia than LIS and percentage of time less than 54mg/dL during week 26 trended lower. In the group of those with A1C less than 8.5%, more “severe” hypoglycemia was reported with HDV-L and time at less than 54 mg/dL during week 26 trended higher.
Additionally, investigators noted that HDV-L and LIS subjects with A1C less than 8.5% showed little difference in bolus/basal dosages at endpoint. Favorable total cholesterol change was noted with HDV-L (-6.5 mg/dL) compared with LIS (+7.3 mg/dL).
Study author Bruce Bode, MD, diabetes specialist with Atlanta Diabetes Associates, sat down with MD Magazine® at ADA 2019 to give his perspective on what the results of the study mean for primary care.
MD Mag: What were the results of Diasome’s study of hepatic directed prandial insulin?
Bode: So, Diasome has a phospholipid that they developed to really drive insulin directly in the liver. Typically, people with diabetes, they inject insulin underneath the skin and so, when you inject it in the skin it goes in the bloodstream but it doesn't really get to the liver. Normal people, who don't have diabetes, they have islet cells, insulin is being released from the pancreas directly into the portal vein which goes right to the liver. So, all of the insulin the pancreas makes goes into the liver and then it goes into the system and then from there it goes from the pulmonary artery and elsewhere in the body.
So, Diasome has developed a way of getting liver specific insulin, that uses this phospholipid, which is a very safe substance. In there is biotin and when they mix insulin with this phospholipid, and it can be any insulin be basal insulin, regular insulin, rapid- acting insulin, it'll bind to this phospholipid in about a hundred molecules of insulin are about a hundred molecules of insulin are binding to these phospholipid discs and there's thousands of these discs that they can put in a vial of insulin and then it becomes hepatic-specific insulin.
So, in our phase 2b trial we got adults with type 1 diabetes and we had we divided them into two groups. If your a1c was above 8.5, see how they worked and if the a1c was below 8.5, see what happened with those people and so it was a fairly large, over 60-plus patients, and they showed that if you had an a1c of 8.5, you would drop your a1c by 0.5 with a reduction in hypoglycemia and this has never been seen in diabetes. That you give insulin and lower it with the reduction in hypoglycemia and this this was a significant difference being both below 70 as well as below 54 and the people said, "Well how could this happen?".
Well, all you need is some insulin to get to the liver, to store glucose, and if you're able to store glucose you decrease the risk of hypoglycemia. You also, in this phase 2b, we dropped the amount of insulin they need — needed upwards of 15 to 20% less insulin you were more effective in driving glucose into the cells without a risk of hypoglycemia. The group that was less than 8.5 had no significant side effects. There was slightly more hypoglycemia in the Diasome group and that's probably due to too much basal insulin.
So, we're going, in our next trial, using less basal insulin but this method of getting insulin using these vesicles, it's called HDV — it's a hepatic directed vesicle — which is this phospholipid. It's able to carry insulin into the liver and when you're able to do this you, not only decrease the amount of insulin you need, you're able to bring the glucose down goal with less risk of hypoglycemia and so it obviously works and so now we're doing a trial, another phase 2b, just getting how much reduction of insulin we need to give to these people to be safe, because it certainly works and the benefit is safety is not an issue. There was no increase in AST or ALT, which are liver enzymes. There was no side effects that we saw. When we looked at lipids, the cholesterol went down, the LDL cholesterol went down, triglyceride went down, and even HDL went slightly down.
So, it's very safe on the liver. It's having no side effects but benefit here for people with diabetes, but we have to prove this in Phase 3. That you can use, this decrease a1c in everyone to goal, with less insulin but with really less hypoglycemia. We aren't really concerned about less insulin, but you decrease your mealtime insulin by about 20% and the basal insulin also probably needs to be decreased.
This is the first time they presented real-time data to the American Diabetes Association. This is a big step for Diasome, they've been working on this for many — I mean a good 15-plus years — because you have to do a lot of animal work, you have to show how this works in with insulin being directed to the liver and so obviously this is something that everybody has been trying to do but, unfortunately, nobody's been able to succeed in doing so into Phase 2 work. A lot of phase one studies have occurred but nobody has brought it to Phase 2 but to get to the market you have to not only get phase 2 to be successful, you got to make sure phase 3 is safe and it's effective and if it shows that you can drop a1c and get people more to goal with less hypoglycemia — that's a great thing and right now there's no safety issues at all.