According to the International Diabetes Federation, as early as 2017, there were 425 million adult diabetics worldwide, and in 2019, the alliance released data showing that there were 463 million people with diabetes worldwide, with a prevalence of about 9.3%. It can be seen that the number of diabetic patients is on the rise, and the corresponding treatment methods have also become an important issue for people.
Many sugar friends are no strangers to metformin, it is a classic hypoglycemic drug that has been clinically used for more than 60 years, the hypoglycemic effect is mainly reflected in improving peripheral insulin resistance, reducing the output of liver glucose, and at present, metformin reduces blood sugar and other effects and potential mechanisms in other disease areas are still being studied.
However, it cannot be ignored that if the effect of metformin is not enough to control the disease, as the disease progresses and over time, most patients with type 2 diabetes may need a combination of 2 drugs if they want to control blood sugar levels. The study published in the New England Journal of Medicine compared 4 commonly used therapeutic drugs approved by the US Food and Drug Administration, and found that the blood glucose compliance time of patients in the combined liraglutide group was extended by more than 6 months!
Let's combine this study with NEJM to learn more about how to choose the "second" drug for diabetes treatment and the sugar control effect of several other commonly used treatment drugs. And how liraglutide, which "stands out" from 4 therapeutic drugs, penetrates the blood-brain barrier.
First, when metformin alone is not enough to control the disease, how to choose the second drug? NEJM study: efficacy can be worse than 6 months
The number of diabetic patients in mainland China can account for more than a quarter of the total population, and the number ranks first in the world is as high as 114 million, so the prevention, diagnosis and treatment of diabetes are very important. Because if diabetic patients can control their blood sugar at normal levels, the risk of diabetes complications will also be significantly reduced, and the impact on health will be reduced to a certain extent.
However, due to the dual factors of disease progression and time passing, most people with type 2 diabetes need to be treated with 2 drugs to control blood sugar within the normal range. As a result, the problem of optimizing the sugar control regimen arises: which drug is the best "second drug". The New England Journal of Medicine focused on this and conducted the longest and largest study comparing the effectiveness of commonly used drugs for type 2 diabetes.
Considering that metformin is a classic treatment for the treatment of type 2 diabetes, the four drugs selected for this study, sitagliptin, liraglutide, insulin glargine, and glimepiride, were used in combination with metformin. The researchers took more than 5,000 patients from 36 research centers in the United States as the study subjects, who were not less than 30 years old, had used metformin during hypoglycemic therapy, and were type 2 diabetes patients with diabetes course less than 10 years.
The study began in 2013, when the average age of patients at the time of joining the study was 57.2 years, and more than half were men. It is worth noting that the four drugs approved by the US Food and Drug Administration selected by the researchers can actually be divided into two categories: oral drugs and injectable drugs, which the researchers compared and randomly assigned participants to 4 different treatment groups.
For example, the treatment regimen of long-acting insulin injection drugs is: metformin + insulin glargine, while GLP-1 receptor agonists are: metformin + liraglutide. The investigators set the primary endpoint of treatment as glucose control therapy failure, and then after an average follow-up of 5 years, the sitagliptin group had the highest treatment failure rate (77%) and the lowest failure rate of insulin glargine (67%).
After analysis, the researchers found that the two drugs of insulin glargine and liraglutide can play a more effective role in maintaining the target range of patients' blood sugar. We need to know that the background of this study is somewhat special, for the relative effectiveness of metformin combination drug in maintaining glycated hemoglobin target levels in patients with type 2 diabetes mellitus is actually unclear, and from the time of this study to maintain glycated hemoglobin standards, sitagliptin is shorter at 697 days, while liraglutide is maintained for up to 882 days.
That is to say, compared with the sitagliptin group, which had the shortest time to achieve blood glucose, patients in the liraglutide group had a longer blood glucose compliance time of more than 6 months, and in terms of weight loss effect and complications, liraglutide showed better levels.
For example, in terms of complications, patients in the liraglutide group had the lowest overall risk of any cardiovascular disease compared to other treatment groups; In terms of weight loss effect, although on average all four treatment groups experienced weight loss, the weight loss of patients in the sitagliptin group and liraglutide group was higher than in the other two groups.
Liraglutide has been approved as an antidiabetic drug, glucosin-like peptide 1 receptor agonist for the treatment of obesity without or with type 2 diabetes, and has a wide range of metabolic benefits. However, previous studies have been difficult to clarify the site and mechanism of action of liraglutide, so how does it penetrate the blood-brain barrier?
A study published in Cell Metabolism explored this problem, in which researchers proved that liraglutide can bypass the blood-brain barrier by intravenous administration and fluorescent labeling of liraglutide. In addition, the transport routes of liraglutide were depicted, and the researchers emphasized the important role of tanycytes.
Specifically, it selectively silences the glucaemia-like peptide 1 receptor in Tanese cells or inhibits Tancyte transport through the expression of toxic neurotoxins, which can not only hinder the activation of liraglutide on hypothalamic target neurons, but also block the anti-obesity effect on weight, food, etc. In other words, the hypothalamic neuronal and downstream metabolic effects induced by liraglutide are mediated by transport to the basal base of the hypothalamus with the help of Tancytes, which also confirms that Tantam cells are key regulators of metabolic homeostasis.
Because 60 seconds after the investigator's jugular intravenous injection, liraglutide did not pass through the microvascular endothelial cells of the BBB, but briefly appeared in the neuronal soma and tanycytes in the ventral middle of the hypothalamic arcuate nucleus through extravasation of the ME foramen vessel. Not only that, liraglutide can also reduce food intake, increase fatty acid oxidation, induce weight loss, and have a certain effect on anti-obesity in people with or without type 2 diabetes.
However, this does not mean that when metformin can not achieve the therapeutic effect, liraglutide can become the first choice, in combination therapy or follow the doctor's advice, after all, in terms of safety, although the above 4 treatment options show a better level, but compared with other treatment groups, liraglutide treatment group patients have a higher risk of gastrointestinal tract.
Third, the diabetes treatment pattern is facing innovation again! Top journal research in the field of diabetes: one dose, 7 days of sugar control
Whether they are type 1 or type 2 diabetes, they need long-term insulin injections to maintain a normal life, but the problem is that it is not a simple behavior. For example, insulin injections should be calculated according to the blood glucose level detected by the continuous blood glucose detection system or blood glucose meter, and in order to maintain the normal blood sugar level, it is necessary to control the intake of carbohydrates in life.
This situation makes about two-thirds of physicians believe that long-term daily insulin injections are a relatively large burden for patients, and most patients receiving insulin therapy also want to achieve good blood sugar control through other means.
On the other hand, previous surveys have shown that compared with 2 injections per day, 1 treatment per week may reduce the burden of diabetic patients while reducing the number of injections, and can also improve the continuity and adherence of treatment, potentially improving clinical outcomes for diabetic patients.
A related study published in The Lancet Diabetes & Endocrinology in May this year said that the safety of weekly insulin icodec treatment and patient satisfaction are considerable. For patients receiving basal insulin therapy but the effect of blood glucose control is not satisfactory, weekly insulin icodec therapy can reduce glycated hemoglobin to a certain extent better than once a day basal insulin therapy, and the treatment goal of glycated hemoglobin <7% may be achieved by more patients in the future.
But what exactly is the insulin icodec that researchers base on this? In fact, insulin icodec is an ultra-long-acting insulin preparation, and its experimental research has gone through several stages.
In previous studies, a single injection of insulin icodec achieved the patient's basal insulin requirement for 1 week, and the hypoglycemic effect was roughly evenly distributed between doses. Subsequently, the results of the phase 2 trial concluded that the treatment of insulin glargine U100 once a day or insulin icodec once a week had similar effects on diabetic patients in terms of safety characteristics and degree of glycemic control. Many people do not know that insulin icodec has a half-life of more than 1 week in the human body.
The researchers randomly assigned more than 500 people with type 2 diabetes to insulin icodec and other groups after 26 weeks of study. This study is significant because weekly insulin icodec treatment has a significant effect in reducing the burden of insulin injections in patients with type 2 diabetes, and also improves overall treatment satisfaction.
Bibliography:
[1] The GRADE Study Research Group.Glycemia Reduction in Type 2 Diabetes — Glycemic Outcomes.2022.09.22.
[2] Hans Christian Cederberg Helms.Tanycytes control hypothalamic liraglutide uptake and its anti-obesity actions.2022.06.17.
[3] Edward Franek, Ting Jia.Switching to once-weekly insulin icodec versus once-daily insulin degludec in individuals with basal insulin-treated type 2 diabetes (ONWARDS 2): a phase 3a, randomised, open label, multicentre, treat-to-target trial.2023.05.03.