Editor's note: As a very powerful hypoglycemic drug, insulin has always played an important role in blood sugar management. However, frequent insulin injections are one of the main reasons for the delay in initiation of daily insulin formulation and poor treatment adherence in patients with type 2 diabetes mellitus (T2DM), which leads to poor glycemic control and increases the risk of long-term complications. According to a global online survey [1], one-third of diabetic patients have poor adherence to insulin therapy, with 59% of physicians citing frequent injections as a major obstacle to adherence to insulin therapy, and 93% of patients on insulin therapy who want to have a good blood sugar control without the need for daily injections.
The world's first weekly insulin insulin insulin (trade name: Novo period ®) was approved for marketing in China on June 24 this year. It meets the ideal needs of doctors and patients for insulin therapy, i.e., only once a week, greatly reducing the number of injections, while still maintaining a strong hypoglycemic safety profile with a low risk of hypoglycemia. In order to help clinicians better understand insulin encor and its latest research progress, at the 84th Annual Scientific Meeting of the United States Diabetes Society (ADA2024), this journal conducted an exclusive interview with Professor Hong Tianpei from Peking University Third Hospital and Professor Tina Vilsbøll from the University of Copenhagen and the Steno Diabetes Center in Copenhagen Denmark for readers.
1. Solve unmet needs: R&D technology continues to innovate, and we are committed to the pursuit of ideal insulin
Prof. Hong Tianpei: Since the development of the field of diabetes treatment, many limitations of human insulin cannot be ignored, so the development of insulin analogues (including prandial insulin and basal insulin) that are closer to physiological insulin secretion and action is the ideal R&D strategy for insulin preparations. Insulin secretion includes basal insulin secretion and insulin secretion during meals, and the main pathophysiological mechanism of diabetic patients is defective and/or defective insulin secretion.
First of all, in terms of mealtime insulin, in general, ordinary insulin is easy to combine with zinc ions to form hexamer, which delays the entry of insulin from the injection site into the bloodstream, thereby delaying its hypoglycemic effect. At this time, the amino acid sequence of insulin can be changed to quickly dissociate from the hexamer into a monomer, which is convenient for rapid absorption, so as to better reduce postprandial hyperglycemia. Second, basal insulin accounts for about 50% of the total insulin secretion throughout the day [2], and the first-generation basal insulin NPH was developed to meet the basal insulin requirements of patients with T2DM and to reduce the number of insulin injections. Although NPH can reduce the number of injections, it has a very obvious "peak effect", which is easy to have a superimposed effect with prandial insulin, increasing the risk of hypoglycemia. Moreover, the role of NPH does not cover the need for basal glycemic control throughout the day, so there is a need to continue to develop more desirable basal insulin analogues.
At present, basal insulin analogues have been greatly improved compared with NPH, and the main methods to prolong the pharmacokinetics of basal insulin include fatty acid acylation, Fc fragment fusion, and polyethylene glycol modification. For example, insulin degludec is combined with albumin through fatty acid acylation technology to form a long chain of polyhexamers, which prolongs the half-life and duration of action. In general, the ideal basal insulin should have a flat action curve, stable efficacy, continuous coverage for 24 hours, minimize blood glucose fluctuations while ensuring glucose-lowering efficacy, and have a small risk of hypoglycemia. This is also an important criterion for evaluating the quality of basal insulin.
2. Ideals into reality: The innovative molecular design of Eco insulin meets the needs of once-a-week administration
Prof. Hong Tianpei: Ecointong is a new type of basal insulin analogue, which is based on fatty acid acylation technology and changing the amino acid sequence, and realizes the frequency of weekly administration. In the molecular structure of insulin enco, a 20-carbon fatty acid side chain is introduced, and the spacer-linker is linked to lysine at the B29 position to obtain a strong and reversible binding ability to albumin. Three amino acid substitutions were performed simultaneously to increase molecular stability, reduce enzyme degradation, and reduce insulin receptor-mediated clearance, resulting in a significantly longer half-life [3]. After subcutaneous injection, insulin eco binds to albumin in the blood circulation to form a reservoir, and then the active insulin eco molecules are slowly and continuously released from the reservoir, acting on target organs and tissues like a "trickle", and the injection is administered once a week to meet the basal insulin requirement for one week. Generally, steady-state can be reached after 3~4 injections[4].
Results from the ONWARDS series of Phase 3 clinical trials that have been completed have shown that once-weekly insulin reduces glycosylated hemoglobin (HbA1c) with better or similar glycosylated hemoglobin (HbA1c), higher or similar glucose target range time (TIR) (up to >70%) in patients with T2DM compared with daily insulin preparations [10], and compliance (HbA1c<7%) and safety compliance (HbA1c). <7% without grade 2 or 3 hypoglycaemia), and the risk of hypoglycemia was not significantly increased (Figure 1). The most prominent thing is that insulin encor not only greatly improves patients' treatment compliance and satisfaction, but also helps patients get rid of the inconvenience and pain of daily injections, and truly realizes the convenience and humanization of diabetes treatment, which is conducive to overcoming clinical inertia and truly bringing benefits to patients' blood sugar control.
Figure 1. ONWARDS 1-5 STUDIES HAVE SHOWN THAT INSULIN ENCO IS MORE EFFECTIVE OR NON-INFERIOR TO BASAL INSULIN DAILY IN LOWERING GLUCOSE, AND THE RISK OF HYPOGLYCEMIA IS COMPARABLE
3. Evidence-based: Ecco insulin for the treatment of T2DM patients has a definite hypoglycemic and good safety profile, and innovation continues
Prof. Tina Vilsbøll: Insulin Eco has been dosed once a week through its innovative molecular design. ONWARDS 1-6 CLINICAL STUDIES, ONWARDS 1-5 ARE BASED ON PATIENTS WITH T2DM AND ONWARDS 6 ARE BASED ON PATIENTS WITH TYPE 1 DIABETES. ONWARDS 1, 3 AND 5 STUDIES WERE CONDUCTED IN PATIENTS WITH T2DM WHO HAD NOT BEEN PREVIOUSLY TREATED WITH INSULIN, AND ONWARDS 2 AND 4 WERE STUDIES IN PATIENTS WITH T2DM WHO HAD RECEIVED PRIOR INSULIN THERAPY, AND THESE STUDIES WERE DESIGNED TO COMPARE THE EFFICACY AND SAFETY OF ONCE-WEEKLY INSULIN INSULIN WITH DAILY PREPARATIONS OF BASAL INSULIN IN PATIENTS WITH T2DM. The results of the study showed that once-weekly injections of 7-fold doses of insulin encor had similar or better reductions in HbA1c and a similar risk of hypoglycemia compared with daily insulin preparations, dispelling our concerns about the risk of hypoglycemia with this new therapy.
At the ADA Annual Meeting, multiple subgroup analysis studies explored the role of insulin eco in patients with T2DM such as glucagon-like peptide-1 receptor agonists (GLP-1RA) at baseline, regardless of age, ethnicity, and baseline. BECAUSE MANY OF MY PATIENTS WERE ALREADY TAKING GLP-1RA PRIOR TO INITIATION OF INSULIN ENCOR, I CONDUCTED A SUBGROUP ANALYSIS OF WHETHER GLP-1RA WAS USED AT BASELINE IN THE ONWARDS 1-5 STUDY [11]. The results showed that the reduction in HbA1c was similar in the insulin group compared with the daily insulin formulation, regardless of whether the patient was taking GLP-1RA (Figure 2, P interaction > 0.05), as well as similar weight changes and insulin doses. In addition, in the ONWARDS 1-3 and 5 studies, the proportion of patients with HbA1c at baseline was <7% and no grade 2 or 3 hypoglycemia was higher in the subgroup with GLP-1RA and the incidence of hypoglycemia was numerically lower in both insulin ecco and basal insulin daily formulations (Figure 3).
Figure 2. ONWARDS 1-5, estimated treatment difference in the reduction of HbA1c between insulin enco and daily preparations of basal insulin based on baseline with or without GLP-1RA
Figure 3. Proportion of patients with HbA1c <7% in daily preparations of insulin enco versus basal insulin in ONWARDS 1-5 without grade 2 or 3 hypoglycemia (%)
In conclusion, these data provide an important reference for clinical application. Once a week is safe and even better than basal daily insulin formulations, the key is that it can be reduced from 365 to 52 injections per year, and I believe that insulin eco will soon be available around the world.
At the end of the interview, Prof. Tina Vilsbøll was looking forward to the combination of basal insulin and GLP-1RA for the treatment of T2DM. She said that in clinical practice, patients are treated in complex contexts, and if they are on once-daily insulin and once-daily GLP-1RA, then they may need multiple injections. As we use, the fixed-dose combination of insulin degludec liraglutide injection (IDegLira) solves the problem of multiple injections, has been proven to be simple and convenient to use, and can achieve synergies due to the complementary mechanisms of action of insulin and GLP-1RA, while the risk of hypoglycemia is small. As a result, she is very much looking forward to seeing the effects of the fixed-dose combination of insulin eco and semaglutide (IcoSema) and expects to see the results of the COMMIT series of clinical trials published at this year's European Association for the Study of Diabetes (EASD) Annual Meeting.
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