Living With Healthy Hunger Health Blog
The history of the emergence and use of insulin began in 1921, when the University of Toronto scientists Frederick Banting and Charles Best for the first time managed to extract an extract from the pancreas that lowers blood glucose levels in dogs with experimental diabetes. An experimental drug was introduced to the first patient in January 1922. Since then, natural insulin preparations have been used in the treatment of diabetes, which were obtained from the pancreas of cattle and pigs. The “first” insulin preparations made it possible to prolong the lives of patients suffering from diabetes, but had quite a few side effects. In 1953, Frederick Sanger deciphered the chemical structure of insulin, which made it possible to improve the quality of the insulin preparations used. But truly, the era of the pharmacological “race” for the best insulin drug began only in 1977 with the discovery of the DNA structure and the introduction of recombinant technologies.
This made it possible to determine individual amino acid sequences in proteins, change them and evaluate the biological effects of the products obtained, which led to the emergence in pharmacology of a whole direction, engaged in the synthesis of new molecules with the improvement of the properties of previously studied substances, drugs. Thus, since the last century, the pharmacological market for insulin preparations has changed significantly – from bovine and porcine through genetically engineered to analog insulin. Insulin preparations currently used differ mainly in four characteristics: origin, rate of onset of action and its duration, method of purification and degree of purity of the preparations, as well as the concentration of insulin. In the mid-1990s. The drug therapy for diabetes included insulin analogues.
One of the insulin preparations recommended for use to achieve the compensation of carbohydrate metabolism in patients suffering from type 2 diabetes is detemir (Levemir®, Novo Nordisk). This is the first acylated analogue of long-acting human insulin (Fig. 1). It is obtained in the process of expression of the recombinant DNA of Saccharomyces cerevisiae, followed by chemical modification. When this happens, the amino acid threonine is removed from position B30 and fatty acid residue consisting of 14 carbon atoms is attached to the amino acid lysine at position B29, C14 (myristic acid), the side chains of which bind to the formation of dihexamers and tissue albumin. Insulin self-association and albumin binding determines the ability to prolong insulin absorption from the depot in the subcutaneous fatty tissue at the injection site.
After subcutaneous administration, due to the active binding to albumin (more than 98%) at the injection site, the serum concentration of insulin detemir in the blood increases more slowly. The maximum serum concentration is reached between 6 and 8 h, while insulin has no pronounced peaks of action. Another distinctive feature of the action of this insulin is the minimal variability of absorption, which allows to avoid significant fluctuations in the level of glycemia and the development of hypoglycemic states, which, in turn, forms the commitment of patients to use this drug for treatment.
Insulin detemir is a sterile, transparent neutral solution with pH = 7.4, which does not form precipitates at the injection site, creating a liquid depot of dihexamers in the subcutaneous fatty tissue. In addition, reversible bonds with albumin are formed, which also contributes to the prolongation of the action. After absorption into the bloodstream, rapid dissociation occurs with the formation of monomers. The circulation also notes a certain prolongation of the action of detemir due to binding to albumin. But this plays a smaller role than the binding of the drug to albumin in the subcutaneous depot.
Another important aspect is the minimal effect of insulin detemir on patient weight. This fact is particularly significant, given the pronounced fat-mobilizing effect of the hormone and the frequent presence of overweight or obesity in patients with type 2 diabetes. Therapy with insulin detemir was accompanied by less dynamics of body weight compared with neutral protamine Hagedorn (NPH insulin), as well as low intraindividual variability of fasting glucose indices. Edith M. Heintjes et al. conducted a retrospective assessment of weight in patients who were on treatment with long-acting insulin analogues (glargine and detemir) and oral hypoglycemic drugs (PSSP) for 3 years (a retrospective analysis of the register PHARMO 2004–2008, the Netherlands). The case histories of 720 patients suffering from type 2 diabetes were analyzed, of which 252 people were treated with insulin detemir and PSSP, and 460 people received insulin therapy with glargine and PSSP. After two years of treatment, weight gain in patients of the first group was 0.2 kg, and in patients of the second group – 1.2 kg.
Similar results were obtained when assessing weight and in patients with type 1 diabetes. Philippe Vague et al. conducted a 6-month comparative study with parallel groups that included 448 people with type 1 diabetes. Patients were randomized into two groups: detemir treated with insulin therapy and NPH in combination with the fast-acting insulin analogue aspart (NovoRapid®) preprandially. By the end of the study, body weight was significantly lower in patients in the insulin detemir group. We also note the lack of weight gain when using insulin detemir twice a day, according to a 16-week study conducted with patients with type 1 diabetes (n = 408). They were randomized to groups that received insulin detemir twice a day in two different regimens: before breakfast and before bedtime or at a 12-hour interval, and NPH insulin, which was administered before breakfast and before bedtime. The ultrashort insulin analogue aspart (NovoRapid®) was prescribed as a bolus insulin. In the NPH insulin therapy group, the patients showed an increase in body weight. In the insulin detemir therapy groups, changes in body weight were not recorded. Thus, the general glycemic control during insulin therapy with Detemir was better compared with NPH insulin therapy, regardless of the mode of administration.
For comparison, insulin detemir and insulin glargine in type 2 diabetes Julio Rosenstock et al. conducted a 52-week international randomized open study in parallel groups. Forty-five percent of patients received the insulin analog detemir 1 time per day and 55% – 2 times per day, depending on the level of glucose in the blood before lunch. Insulin glargine was administered 1 time per day. The effect on the glycemic control and the frequency of hypoglycemia showed no significant differences between the drugs. In the group of patients who received insulin detemir, there was a significantly lower weight gain compared with the group of patients who were on the insulin analogue glargine, 3.0 and 3.9 kg, respectively. The authors concluded that both drugs improve the control of blood glucose levels, however, insulin detemir has some advantage regarding the dynamics of body weight.
Louis Monnier et al. found that in patients with type 2 diabetes with a progressive deterioration in glucose control, postprandial control is more impaired. Many patients have inadequate glycemic control due to fear of hypoglycemic conditions and / or against the background of their development. Insulin analogues are non-peak insulins, which significantly reduces the risk of developing these conditions. In all studies when comparing NPH insulin and insulin analogues, less hypoglycemic states are observed during therapy with insulin analogues. A number of comparative studies to assess the frequency and severity of hypoglycemia in the use of long-acting insulin analogues were conducted.
Thomas R. Pieber et al. conducted a multicenter open study in parallel groups, in which 320 patients with type 1 diabetes who received short-acting insulin during a meal and insulin detemir 2 times a day or an insulin glargine analogue 1 time per day took part. Patients performed self-monitoring of glycemia. It was noted that blood glucose levels were lower in the group on the insulin analogue glargine than in the group that used the insulin analogue detemir (7.0 mmol / l and 7.7 mmol / l, respectively; p <0.001), but the differences in terms of glucose, measured at 9 points during the day, was not. Blood glucose fluctuations in the insulin detemir group were lower before dinner (p <0.05). The overall incidence of hypoglycemia between the groups did not differ, but in the insulin detemir group, the incidence of severe hypoglycemia was 72% lower, and nocturnal hypoglycemia was 32% lower than in the insulin glargine group (p <0.05). This confirms that the insulin analog detemir provides a flat and prolonged pharmacodynamic profile with a high interindividual predictability of action. In the insulin glargine group, there was a large increase in body weight (0.96 kg) than in the insulin detemir group (0.52 kg), but the difference was not statistically significant (p = 0.193).
In 2007–2008 The results of the international open prospective PREDICTIVETM study, which was conducted to assess the safety and efficacy of insulin detemir in routine clinical practice, were published. The study involved more than 30 thousand patients with type 1 and type 2 diabetes who started treatment with insulin detemir. In a cohort that included 20,531 patients from 11 countries of the world, 214 serious adverse events were recorded at the start of insulin detemir treatment, among which was marked hypoglycemia. However, when compared with previous therapy, insulin detemir treatment was accompanied by a statistically significant reduction in the incidence of serious hypoglycemia from 3 to 0.7 episodes per patient per year, as well as a significant decrease in HbA1c levels, fasting glucose, body mass and fluctuations in blood glucose levels. At the same time, 49% of patients with type 1 DM and 77% of patients with type 2 DM received the insulin analog detemir 1 time per day, and 50 and 23% of patients, respectively, 2 times a day. 9 cases of common adverse events were noted, of which 6 were local skin reactions. In patients with type 2 diabetes who previously received insulin glargine, insulin detemir significantly reduced HbA1c levels, blood glucose variability and body weight. In patients with type 1 diabetes who were part of the European cohort, the replacement of insulin glargine with insulin detemir also led to a significant decrease in HbA1c, fasting glucose and fluctuations in glucose, but there were no differences in body mass.
Of undoubted interest is the summary table given in Allen B. King, which includes the results of various studies on the assessment and comparison of NPH insulin and analog insulin glargine and detemir. Thus, the main distinguishing features of insulin detemir are significantly less effect on weight gain, less variability of glucose levels and less frequency of hypoglycemia.
When and to whom can we confidently recommend therapy with the insulin analog detemir? First of all, patients with type 2 diabetes mellitus, who need to start insulin therapy with subsequent possible intensification, who are focused on measuring fasting blood glucose and who are overweight. The need for compliance with diet and exercise is obvious for patients with diabetes and is the first step in the treatment of this disease. However, to achieve compensation of carbohydrate metabolism only when these conditions are met is almost impossible. This is partly due to the behavior of patients (“to know does not mean to comply with”), but more often, especially with type 2 diabetes, with late diagnosis of this disease.
Compensation criteria vary by country. Thus, according to the recommendation of the American Diabetes Association (ADA), the target plasma glucose level on an empty stomach should be 5.0–7.2 mmol / l, the plasma glucose level after eating (at any time!) Should be less than 10.0 mmol / l. The American Association of Clinical Endocrinologists (AACE) recommends that fasting plasma glucose (HPP) should be less than 6.1 mmol / l, plasma glucose after eating (after 2 hours) less than 7.8 mmol / l. The International Diabetes Federation (IDF) prescribes a fasting plasma glucose level of less than 5.5 mmol / l, plasma glucose level after a meal (after 2 hours) less than 7.8 mmol / l. Targeted values of НbА1с are significantly different: ADA – 7%, AACE – 6.5%, IDF – 6.5%.
For the Russian Federation, the criteria for compensation of carbohydrate metabolism are HbA1c levels of less than 7%, HBL less than 6.5 mmol / l in capillary blood. The first step in the treatment of diabetes is diet therapy, the normalization of weight and increased physical exertion. In the absence of a sufficient effect, MSSPs of different groups are added at the second stage. It should be noted that most drugs stimulate glucose-independent insulin secretion and can “lead” to the depletion of β-cells. In addition, many of them have a long period of action (more than 12 hours), which, in turn, leads to an increase in appetite, weight gain and increased insulin resistance.
Most patients were on PSSP therapy, and only 14.2% were on insulin therapy. It is reliably known that insulin has a protective effect on β-cells and, with rational dose selection, it leads to compensation of carbohydrate metabolism with a relatively intact body mass. Timely administration of insulin contributes to the improvement of the glycemic profile, both lean and postprandial. With the development of type 2 diabetes, not only phase 1 of insulin secretion is disturbed, but also basal production. For these patients, it is often sufficient to restore normal basal insulin levels for possible correction of postprandial glycemia. It is advisable to start insulin therapy with a HbA1c level of more than 7.5% or with fasting glucose more than 7.5–8.0 mmol / l (against the background of previous therapy with maximum doses or a combination of PSSP). The initial dose of therapy with insulin detemir is determined by pharmacological properties. According to the recommendation of the manufacturer (“Novo Nordisk”), it is 0.2 U / kg body weight.
Several studies have been conducted to determine the optimal dose at the start of therapy with the insulin analog detemir. Based on the data obtained and our experience, it may be recommended to start therapy with the insulin analog detemir with 10–12 IU once a day or with recalculation to a body weight of 0.2–0.4 IU per kilogram of real weight, but not more than 15 IU when starting therapy in one injection. Dose titration should be carried out once a week (± 2–4 U) until reaching the target values (fasting glucose from 5.0 to 6.5 mmol / l). Our data are consistent with those of Lawrence Blonde et al., Which indicate that 64% of patients reached HbA1c levels below 7% when titrating the dose of analog insulin detemir administered once a day. In some cases, it may be recommended to carry out a correction (reduction of doses) of PSSP taken and / or a change in the group of these drugs. Given the minimal risk of developing hypoglycemic conditions, detemir is best suited for older patients, as well as patients of any age, leading an active lifestyle.
Conclusion
- The insulin analogue of the prolonged action of detemir is optimal for the correction of the glycemic profile in patients with type 2 diabetes.
- The purpose of this therapy is optimal in the absence of compensation of carbohydrate metabolism on the background of compliance with the diet and exercise and the use of PSSP.
- The use of insulin detemir in optimal doses, with proper titration, practically does not cause the development of hypoglycemic states.
- This drug does not contribute to weight gain.
- The achievement of compensation of carbohydrate metabolism is possible with the appointment of insulin detemir once a day.
