Insulin analogues in clinical practice

If it were not for the devastating effects of hypoglycemia, treating diabetes would be very easy. F. Kreyer

One of the oldest diseases, in terms of clear descriptions of symptoms, is diabetes mellitus (DM). Hippocrates also paid attention to sweet urine in young people who suddenly lose weight, drink a lot and secrete fluid, and quickly die for unknown reasons. For many centuries, doctors only noted the presence of this disease, but could not help the patient. In 1921, Drs F. Banting and G. Best were the first to obtain an extract from the pancreas of dogs, which eliminated hyperglycemia and glycosuria in such patients. A year later, the first commercial insulin preparations were prepared. But the real era of the pharmacological “race” for the best insulin preparation began only in 1953, when Sanger deciphered the chemical structure of insulin. Over these decades, the pharmacological insulin market has changed significantly - from bovine and porcine insulins through genetically engineered insulins to analogue insulins. They will be discussed in this article.

Diabetes is one of the most common diseases among endocrinopathies. The main objectives in the treatment of this pathology are maintaining a normal level of glycemia and preventing the occurrence and development of late complications, as well as preventing hypoglycemia.

The pathogenesis of this disease is based on two endocrine defects: impaired insulin production and peripheral resistance to the action of insulin. It is insulin resistance that causes excess hepatic glucose production, manifested, in particular, by morning hyperglycemia. The creation and implementation of new forms of insulin with improved pharmacokinetic and pharmacodynamic properties is one of the ways to achieve better glycemic control and prevent the development of hypoglycemic conditions. A previously developed regimen of intensive insulin therapy using long- and intermediate-acting insulins makes it possible to achieve relative normoglycemia, but at the same time increases the risk of developing hypoglycemia both during the day and at night. Long-acting and intermediate-acting insulins are characterized by maximum concentrations 5–7 hours after administration, which increases the risk of hypoglycemia at night. The accuracy of NPH insulin dosing varies widely due to inadequate resuspension.

Short-acting human insulin has a slow onset and longer duration of action than endogenous insulin. The administration of both drugs (basal-bolus therapy) is accompanied by significant fluctuations in postprandial and night-time glycemia. When creating insulin analogues, the main goal was to achieve maximum proximity in time and intensity of action to endogenous insulin.

Type 2 diabetes is a progressive disease. The phase of insulin hypersecretion is replaced by a phase of “exhaustion”; during this period, insulin deficiency occurs and the patient begins to need insulin therapy.

Many studies have been devoted to studying the influence of glycemia on the formation of late complications of diabetes. Recently, more and more attention has been paid to the study of postprandial glycemia. A long-term comprehensive study NHANES (National Health and Nutrition Examination Surveys) in the USA shows that even with satisfactory compensation of diabetes, according to glycosylated hemoglobin (HbA1c), hyperglycemia after meals is common. The European epidemiological study DECODE (The Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe) showed that postprandial hyperglycemia is more closely correlated with increased overall mortality than fasting hyperglycemia. Numerous studies have proven the increasing risk of acute vascular disorders against the background of postprandial hyperglycemia: the risk of myocardial infarction and stroke, which cause approximately 70% of deaths in people suffering from type 2 diabetes, increases significantly.

Hypoglycemia is one of the most common and severe complications of diabetes treatment. According to the latest data, hypoglycemia corresponds to the level of glucose in venous blood plasma ranging from 3.5 to 2.8 mmol/l, with the significance of clinical manifestations of hypoglycemia, such as severe sweating, hand tremors, dizziness, a strong feeling of hunger, disturbances in the emotional state , diabetologists neglect.

The causes of this condition may be the following factors:

skipping meals;
inconsistency between meal times and the use of glucose-lowering drugs (insulin administration);
insulin overdose;
excessive physical activity;
drinking alcohol.

Modern science has reached such heights that yesterday’s “dream” of obtaining genetically engineered human insulin and its widespread use has set a new goal for developers: to obtain insulin with parameters superior to some indicators of human insulin. Limitations in the use of short-acting human insulin are: slow onset of action (the patient is forced to administer it 30–40 minutes before meals), prolonged action, sometimes up to 12 hours (increased risk of late hypoglycemia). In the early 1980s, the development of insulin analogues without the above-mentioned disadvantages became relevant. With regard to short-acting insulins, the half-life was maximally reduced, which brought them closer to the pharmacodynamics of native insulin, the inactivation of which occurs 4-5 minutes after entering the portal system. Peakless insulin analogues are able to be gradually and evenly absorbed from the subcutaneous depot and do not cause nocturnal hypoglycemia. The most progressive discoveries of recent years: the transition from acidic insulin solutions to neutral ones, the production of human insulins using DNA recombinant technology, the creation of analogues of human insulin with qualitatively new pharmacological properties.

Analogs modify the action time of human insulin to provide a physiological approach to insulin therapy and are more convenient for the patient to use. They provide an opportunity to achieve a balance between achieving target glycemia and minimizing the risk of hypoglycemia.

Modern analogues of insulin are divided into ultra-short and long-acting based on their duration of action. There are also combined analog preparations, which contain a mixture of ultra-short-acting and long-acting insulin in a fixed ratio. The first include: Humalog, Novorapid Penfill and Apidra. Long-acting ones include Lantus and Levemir Penfill. Combined drugs - penfill, humalog mix 25.

Insulin lispro (Humalog) . In the structure of humalog, the position of lysine and proline in the 28th and 29th positions of the B chain, respectively, is changed, which is accompanied by a significantly weaker spontaneous intermolecular association than that of soluble human insulin. Because of this, Humalog is absorbed much more quickly from subcutaneous injection sites.

A study of insulin concentrations when administering human short insulin and Humalog to healthy volunteers showed that when the drugs are prescribed in the same dose and at the same time, the peak concentration of Humalog is achieved faster and is 2 times higher compared to human insulin. In addition, the drug is eliminated faster and after 4 hours the concentration of humalog returns to its original values, while the concentration of simple human insulin remains within 6 hours.

When comparing the insulin analogue lispro and short-acting insulin, it was noted that humalog suppresses hepatic glucose production significantly more (Fig. 1).

This is more consistent with the physiological early peak of insulin secretion. Thus, humalog causes a greater reduction in the risk of developing persistent postprandial hyperglycemia.

Another advantage of insulin lispro over regular human short-acting insulin, which essentially makes insulin action more predictable and therefore easier to adapt the dose to food load, is that the duration of action of the drug does not change with increasing dose. It is well known that when using simple human insulins, their duration of action can increase depending on the dose, hence the average duration of action is 6–8 hours, and sometimes up to 12 hours (Fig. 2). The study showed that with increasing doses of insulin lispro, its duration of action remains virtually unchanged and is a maximum of 5 hours, while the duration of action of simple insulin increases greatly at higher doses. Thus, increasing the dose of insulin lispro does not increase the risk of late hypoglycemia.

Insulin aspart (novorapid penfill) . Novorapid was obtained by replacing proline in the 28th position of the B chain with asparagine, which also contributed to the acceleration of the dissociation of insulin hexamers into monomers and their rapid absorption from subcutaneous fat.

This insulin preparation more adequately mimics the normal insulin response to food. Its short period of activity results in a weak effect between meals, which allows for more complete glycemic control after meals.

The results of the comparative effect of basal-bolus therapy with insulin analogues (insulin detemir and insulin aspart) with traditional human insulins (NPH insulin and short-acting human insulin) demonstrated a significant improvement in the quality of postprandial glycemic control (Fig. 3).

This study demonstrated that combination therapy with insulin detemir and aspart can almost completely normalize the daily profile of the hormone, improve glycosylated hemoglobin, significantly reduce the risk of hypoglycemia, and there was a significant decrease in the number of peaks and amplitude of fluctuations in blood glucose concentrations. The average body weight of patients on basal-bolus therapy with insulin analogues (detemir and aspart) was characterized by a significantly smaller increase during follow-up.

Insulin glulisine (apidra) . Apidra is an analogue of human ultra-short-acting insulin, in which in the 3rd position of the B-chain, asparagine is replaced by lysine, and in the 29th position of the B-chain, lysine is replaced by glutamine. In terms of pharmacodynamic and pharmacokinetic properties, as well as in its bioavailability, insulin glulisine corresponds to humalog, and in terms of mitogenic and metabolic activity it does not differ from simple human insulin, which allows its safe and long-term use.

As usual, Apidra should be used in combination with long-acting insulin or a basal insulin analogue. Apidra has a faster onset and shorter duration of action than regular human insulin (regular) and allows patients with diabetes to have greater flexibility in using mealtime insulin than regular regular insulin. The drug begins to act immediately after administration. In this case, the glucose level begins to decrease 10–20 minutes after subcutaneous administration of the drug. To prevent hypoglycemic conditions in older people, it is recommended to administer the drug immediately after meals or directly during meals.

The short duration of action of the drug (3 hours) avoids the “overlapping” effect; thus preventing the development of hypoglycemic conditions. The drug can be used in people with excess body weight, since its use is not accompanied by further weight gain. The drug is characterized by a faster onset of peak action compared to regular insulin and even insulin lispro.

Apidra provides greater flexibility in use in those patients whose body mass index varies from overweight to severe obesity. Visceral obesity can affect the rate of insulin absorption, making prandial glycemic control difficult.

Insulin detemir (levemir penfill) . Levemir Penfill is an intermediate-acting analogue of human insulin, has no peaks of action and provides basal glycemic control for 24 hours when administered twice. After subcutaneous administration, detemir forms di-hexamers, which, through the C14 fatty acid chain, bind to serum albumin already in the interstitial fluid. After transport through the capillary wall, the drug rebinds with albumin in the circulating blood. Since only the free fraction of detemir is biologically active, its binding to albumin and subsequent slow dissociation ensures a prolonged and peak-free effect. Levemir Penfill is characterized by a smooth action and meets the patient's need for basal insulin. It does not require shaking immediately before administration [14, 20].

Insulin glargine (lantus) . An ultra-long-acting drug - lantus - was obtained by replacing asparagine at position 21 of the A-chain with glycine, in addition, two molecules of arginine were added to the C-terminus of the B-chain at positions 31 and 32. These changes led to a shift in the isoelectric point of the molecule from pH 5.4 to 6.7, therefore, the solubility of the drug decreased at the physiological values of the neutral environment of subcutaneous tissue. Thus, lantus is completely soluble in a slightly acidic environment, but poorly soluble in the neutral environment of subcutaneous fat. After administration, lantus enters into a neutralization reaction with the formation of microprecipitates, from which insulin glargine hexamers are subsequently released and dissociated to form insulin dimers and monomers. This ensures the gradual release of the hormone into the blood and its circulation in the bloodstream within 24 hours, which allows it to be administered once a day. The addition of a small amount of zinc ensures crystallization of insulin glargine in the subcutaneous tissue, further lengthening the absorption time.

All of the listed features of this insulin analogue determine its smooth “peakless” action profile. The onset of action after subcutaneous administration is 1 hour; a stable concentration of insulin in the blood is achieved 2–4 days after the first administration of the first dose. Regardless of the time of administration of Lantus (morning or evening) and the site of administration (subcutaneous tissue of the arm, leg or abdomen), the average duration of action is 24 hours [5], the maximum duration is 29 hours. The insulin analogue glargine corresponds in effectiveness to physiological insulin: it stimulates Glucose uptake by insulin-dependent peripheral tissues, especially muscle and fat, inhibits gluconeogenesis, thereby reducing blood glucose. In addition, insulin glargine, like endogenous insulin, suppresses lipolysis in adipocytes and proteolysis, increasing protein synthesis (Fig. 4).

Studies of the pharmacokinetics of lantus have proven an almost peak-free distribution of the drug, which makes it possible to most accurately simulate the “basal” secretion of endogenous insulin during the day, significantly reducing the risk of hypoglycemia and the variability of glucose concentrations. A comparison of the pharmacokinetics of insulin Lantus, NPH insulin and Ultralente insulin is presented in Figure 5.

The prescription of long-acting insulin analogues is justified in both type 1 diabetes and type 2 diabetes. The main difference between these drugs is the absence of body weight gain during therapy and a decrease in the number of nocturnal hypoglycemia. It is important to administer this insulin analogue once a day. Many studies have been conducted to prove the effectiveness and safety of this drug. Among them, it is worth noting LANMET on the use of the insulin analogue glargine in combination with metformin in patients suffering from type 2 diabetes and obesity [5]. This study revealed a significant decrease in nocturnal hypoglycemia, which reliably normalizes the level of daily glycemia.

There are also a number of studies devoted to combined therapy with lantus and oral hypoglycemic drugs (OHDs) in decompensated patients. The authors of these works confirmed the previous conclusions and proved the advisability of earlier administration of insulin glargine [6, 9, 19]. The more recent ATLANTUS trial demonstrated the feasibility of initiating lantus therapy when treated by both an endocrinologist and a general practitioner. In the Moscow study, conducted under the leadership of M. B. Antsiferov, it was shown that intensification of initial therapy (PSSP, NPH insulin) with the addition of lantus improves glycemic control in all groups [1].

Humalog mix 25. Humalog mix 25 is a mixture consisting of 75% protaminized suspension of insulin lispro and 25% insulin lispro (humalog). This insulin analogue is a drug with a time-combined release mechanism. The average duration of action is provided by a protaminized suspension of insulin lispro, which imitates basal insulin secretion, and 25% insulin lispro is an ultra-short-acting component and reduces the level of glycemia after meals. It is important to know that Humalog in the mixture acts much faster compared to short-acting insulin, provides better control of postprandial glycemia [18] and thus a more physiological profile compared to short-acting insulin [4, 3, 10, 15, 18] . Mixed insulins are recommended for use in patients suffering from type 2 diabetes. This group includes older people and, for the most part, those with reduced memory. Therefore, the ability to administer insulin immediately before or immediately after a meal is extremely important for them and greatly improves their quality of life. In a study conducted in patients with type 2 diabetes in the age group of 60–80 years, using Humalog Mix 25 administered immediately before and after meals, it was possible to achieve good compensation of carbohydrate metabolism with a slight weight gain and a fairly low incidence of hypoglycemia [7].

Figure 6. Comparison of the effectiveness of Humalog Mix 25 and Lantus in patients receiving metformin

Studies comparing the effects of Humalog Mix 25 and Humulin M3 showed that analog insulin reduces postprandial glycemic fluctuations by 40% more effectively than a ready-mixed human insulin [2]; in addition, the glucose-lowering effect was not dependent on meal time. The latter was confirmed in a very interesting and original study conducted with the participation of patients observing the Muslim fast of Ramadan. During this fast, according to religious laws, food can only be taken after sunset and before sunrise. Thus, patients were able to eat twice a day. Patients received Humalog Mix 25 immediately before meals or Humulin M3 30–40 minutes before meals. Daily monitoring of glycemic levels showed that lower levels of postprandial glycemia and glycemia before evening administration of the drug were in the group of patients receiving Humalog Mix 25. Morning glycemia values did not differ significantly [11]. This work proves that lispro, which is part of this analogue, corrects the level of postprandial glycemia more physiologically. In 2004, a 32-week randomized, open-label crossover study was conducted comparing the effects of Humalog Mix 25 (administered 2 times a day) and the long-acting insulin analogue Lantus (administered 1 time per day) while taking metformin (Fig. 6, 7).

No significant deviations in glycemic fluctuations after lunch were detected, but there was a significant decrease in glycemic fluctuations after breakfast by 65% and after dinner by 70% with the use of Humalog mix 25. In the same group, the incidence of mild hypoglycemia was higher [12]. Work on the comparative effects of these analogues was continued in a study that confirmed a decrease in glucose level fluctuations against the background of Humalog Mix 25 by 25%. Severe hypoglycemia was not reported in any study [13].

Figure 7. Comparison of the incidence of hypoglycemia during treatment with Humalog and Lantus

The dose of insulin depends on the level of glycemia, HbA1c level, and body weight. Insulin therapy should be started with small doses to prevent hypoglycemia. According to the recommendation of the Federal Target Program "Diabetes Mellitus", 12 units of insulin should be administered before breakfast and 8 units before dinner, under glycemic control; if necessary, the dosage is increased by 2-4 units after 2-3 days. If the patient has previously received Humulin M3, then the initial dose of Humalog Mix 25 will be 1: 1. The more overweight the patient is, the more pronounced the insulin resistance and the higher the need for insulin doses. The initial dose in such patients is 0.4–0.8 U/kg/day. Typically, the insulin analogue Humalog Mix 25 requires a 50:50 ratio for morning/evening administration.

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A. M. Mkrtumyan , Doctor of Medical Sciences, Professor A. N. Oranskaya , Candidate of Medical Sciences MGMSU, Moscow

Insulin lispro and pump therapy in children and adolescents

There was a resurgence of enthusiasm for the use of CSII following the publication of the DCCT results. The effectiveness and safety of pump therapy were initially assessed in a National Institute of Health (NIH)-supported study by Weinzimer et al. called ABC (Adolescents Benefit from Control). One of the aims of this study was to determine whether the DCCT recommendations for intensified insulin therapy could be achieved in one large group of adolescents at one center. The study also asked whether increased barriers to intensified insulin therapy may have adverse psychosocial effects in adolescents [2]. At the debut of this study, all patients received 2 insulin injections daily. As in the DCCT, the 75 patients enrolled in the study were allowed to choose their own intensified insulin therapy regimen: 25 chose CSII therapy and 50 patients chose MDI (Multiple Doses Injections) (i.e., 3 or more daily injections). Both patients receiving CSII and MDI therapy initially demonstrated better metabolic control in the first six months of the study. However, this level of carbohydrate compensation was more difficult to maintain with MDI therapy—mean HbA1c levels were higher compared with patients receiving CSII therapy at 12 months (8.3% vs. 7.5%). Most significant were the findings of a lower rate of severe hypoglycemia (50% less with CSII compared with MDI therapy), while HbA1c levels were also lower in the CSII group. Overall, psychosocial well-being improved in both groups of adolescents. However, patients on CSII therapy felt that they had an easier time managing their diabetes. Based on these comparisons with MDI therapy, it was concluded that CSII therapy may provide safer and easier achievement of intensive care goals in adolescents with type 1 diabetes. Interpretation of the ABC Study results is limited by the small number of patients, the inability to include children under 12 years of age, and the study environment in which it was conducted. It should also be noted that all adolescents in the study by Weinzimer et al. have been using regular insulin, while many of the patients on CSII therapy are currently using insulin lispro. In adult patients receiving CSII therapy, insulin lispro showed lower HbA1c levels and a reduced risk of hypoglycemia compared to regular insulin [3]; this is explained by a faster onset and shorter duration of action [4]. These features of insulin lispro are even more beneficial in adolescents, since children with type 1 diabetes require large bolus doses of insulin before meals to overcome pubertal insulin resistance. Based on the successes of ABC, a multidisciplinary team began to implement more intensive use of CSII in pediatric diabetes practice. Thus, the number of patients using CSII therapy is growing at a very fast pace, and all of them are using ultra-short-acting insulin analogues. The latest report described the clinical results of the first 161 patients (aged 18 months to 18 years) in whom CSII therapy with insulin lispro was initiated at the Pediatric Diabetes Center starting in 1997 [5]. Only patients with type 1 diabetes who had been on insulin pump therapy for at least 1 year were included in the study, and their clinical data were collected prospectively (before and after initiation of CSII therapy) using standardized forms and a database developed for this purpose. goals. Of the 161 children included in the study, 26 were preschool-age (<7 years), 76 were schoolchildren (7–11 years), and 59 were adolescents (12–18 years). Before starting CSII therapy, the average HbA1c level was 7.1% in preschoolers, 7.8% in schoolchildren, and 8.1% in adolescents. There was a statistically significant reduction in mean HbA1c levels of 0.6–0.7% after 12 months of CSII insulin lispro therapy in all three groups. This HbA1c level was maintained at the last visit, 32 ± 9 months after the start of CSII therapy (Fig. 1). Improved diabetes control was achieved with CSII insulin lispro therapy without increasing the daily insulin dose and was associated with a 32% reduction in the incidence of severe hypoglycemia. The greatest reduction in the incidence of severe hypoglycemia was observed in the group of preschool children. Based on these data, it was concluded that CSII therapy with insulin lispro is an effective alternative to injection therapy in a large pediatric diabetes clinic, and even in the youngest patients, CSII can be used to safely lower HbA1c levels. The number of children and adolescents using CSII in the diabetes clinic continues to increase. 54.7% of patients (i.e. 512 of 936 children) use pump therapy with good results. The final HbA1c level in patients on pump was 7.3±1.2% (mean±SD), while in patients receiving injection therapy it was 7.8±1.6%. More than 95% of children who were started on pump therapy remained on it after the last clinic visit. In a study by Melki et al. [17] compared the efficacy and safety of insulin lispro versus insulin actrapide in 39 patients using insulin pump therapy. There was a significant decrease in the level of glycated hemoglobin HbAc, glycemia and, most importantly, postprandial glycemia; however, the number of hypoglycemic episodes was reduced. In an open-label, randomized, crossover study, Renner et al. [18] evaluated the use of insulin lispro compared with regular insulin in 113 patients with type 1 diabetes on insulin pump therapy. A more pronounced decrease in the level of glycated hemoglobin was observed in the group using insulin lispro (Fig. 2). Maniatis et al. from the Barbara Davis Center in Denver reported on their clinical experience with the use of CSII therapy in children and adolescents with type 1 diabetes using insulin lispro as basal-bolus therapy [6]. Data from 56 patients were collected during regularly scheduled visits at the same frequency as those not receiving CSII therapy. There was a statistically non-significant decrease in HbA1c levels from 8.5 to 8.3%, before and during CSII therapy with insulin lispro. However, the incidence of severe hypoglycemia before and after initiation of pump therapy decreased from 12.3 to 9.5 cases per 100 patients per year; a statistically significant percentage of patients experienced a reduction in the incidence of milder hypoglycemia. There was no clinically significant increase in body mass index, even in patients with better metabolic control. Similarly, Plotnick et al. reported a slight decrease in HbA1c levels and a sharp decrease in the frequency of hypoglycemic episodes in 95 young people in whom insulin pump therapy with insulin lispro was initiated at Johns Hopkins University [7]. Reducing the risk of severe hypoglycemic episodes was also one of the main benefits of insulin pump therapy in more than 100 children and adolescents who received this therapy at the University of Western Australia [8]. The University of Colorado team also demonstrated some of the benefits of the alternative bolus insulin delivery features used in the current generation of insulin pumps. Insulin lispro was used in this study. “Double wave,” a type of insulin bolus, provides more effective control of postprandial glycemic fluctuations after ingestion of fatty and high-carbohydrate meals than a standard bolus dose administered before or after a meal [9]. Kaufman et al. reported the results of using an insulin pump only at night in children under 10 years of age [10]. The starting point of this study was that a group of children aged 7–10 years could not use an insulin pump at school in the absence of a nurse, but could use it at home under parental supervision. Ten children with type 1 diabetes were randomized and enrolled in a crossover study after 6 weeks of treatment with both insulin delivery routes (CSII therapy used overnight insulin lispro plus insulin injections during the day versus injection therapy alone (lispro and NPH insulin). When compared, better control was noted with the use of CSII. It was concluded that the use of CSII only at night may be recommended for children who are unable to independently operate an insulin pump. Of course, alternative routes exist, such as organizing and training school staff and health care workers handling of an insulin pump when the child's parents and loved ones are unavailable. In the experience of Weinzimer et al., parents of young children with type 1 diabetes can always be reached by mobile phone or pager. Subsequently, the results of treatment of 65 children who were less than Pump therapy using insulin lispro was started for 7 years at the Pediatric Diabetes Center [11]. HbA1c levels decreased from 7.4 ± 1.0% to 7.0 ± 1.0% in the first year of pump therapy, and this level was maintained for more than 48 months. Reducing the incidence of severe hypoglycemia by more than 50% is a very important aspect of the use of CSII therapy in children of this age group. The same improvement in carbohydrate metabolism was achieved in children with both working and non-working parents. Parents of the youngest children noted that CSII therapy improves quality of life and reduces the fear of being enslaved to diabetes control [12]. Safety and Efficacy of CSII in Children and Adolescents: Randomized Clinical Trials When looking at the recent increasing use of CSII therapy in children, it is not surprising that randomized trials comparing CSII and MDI are relatively rare. The first randomized trial comparing the two therapies was conducted in patients with newly diagnosed diabetes. Although b-cell function was virtually absent, HbA1c levels were significantly lower in the CSII therapy group [13]. Weintrob et al. used a randomized, crossover design to compare CSII therapy (using insulin lispro) with a 4-times-daily insulin regimen (using regular and NPH insulins) [14]. Twenty-three children aged 9–13 years were enrolled in a study using both treatments for 3.5 months each. Changes in HbA1c levels were similar for both treatments, and there were low rates of side effects for each treatment. However, patients reported greater levels of treatment satisfaction on CSII insulin lispro therapy compared with MDI, and 16 of 23 patients chose to use pump therapy after the end of the study. In a study by Lepore at al. The pharmacokinetics and pharmacodynamics of the peakless insulin analogue, NPH insulin, Ultralente, and insulin lispro used in pump therapy were studied. [15]. According to its results, the least variability of absorption was noted when using insulin pumps. The overall conclusion from non-randomized and randomized trials summarizes the evidence for the effectiveness of CSII therapy with insulin lispro in children and adolescents with type 1 diabetes in all age groups. However, there is no single treatment approach that is ideal for every patient. The availability of many therapeutic options allows pediatric diabetes clinicians to select the best treatment for each individual patient at any given time. Indeed, the dedication, skill, and enthusiasm of a multidisciplinary team play a primary role in the success of treatment. At this center, diabetes nurses (all highly trained practitioners) are key team members who interact most frequently with patients and their parents [16]. These nurses remain in close contact with patients' family members between visits, communicating by phone, email and fax to adjust treatment regimens and maintain gains. Other key team members include a dietitian, a social worker, and a pediatric endocrinologist. Conclusion. Thus, insulin pumps are currently the most effective tool for managing diabetes. When comparing the effectiveness of using insulin lispro, as an analogue of ultra-short-acting insulin, showed better results in reducing fasting glycemia, postprandial glycemia, glycated hemoglobin levels, and reducing episodes of hypoglycemia compared to short-acting insulins.

References 1. DCCT Research Group. The effect of intensive diabetes treatment on the development and progression of long–term complications in adolescents with insulin–dependent diabetes mellitus. The Diabetes Control and Complication Trial. J Pediatr 1994; 125:177–88. 2. Boland FA, Gray M, Frederickson L, Tamborlane WV. CSII: a “new” way to achieve a strict metabolic control, decrease severe hypoglycemia and increase coping in adolescents with type 1 diabetes. 3. Zinman B, Tildersley II, Chiasson TJ, Tsue F, Strack T. Insulin Lispro in CSII: results of double–blind crossover study. Diabetes. 1997; 46:440–3. 4. Howey DC, Browsher RR, Brunelle RI, Woodworth JR. A rapidly absorbed analogue of humal insulin. Diabetes 1994; 49:2142–8. 5. Ahern JH, Boland EA, Doane R, Ahern IJ, Vincent M et al. Insulin pump therapy in pediatrics: a therapeutic alternative to safely lower therapy HbA1c levels across all age groups. Pediatric Diabetes 2002;3:10–15. 6. Maniatis AK, Klingensmith GJ, Slover RH, Mowry CJ, Chase HP. Continuous subcutaneous insulin infusion therapy for children and adolescents: an option for routine diabetes care. Pediatrics 2001;107:351–6. 7. Plotnick, MD1, Loretta M. Clark, RN, BSN, CDE1, Frederick L. Brancati, MD, MHS2,3,4 and Thomas Erlinger, MD. Safety and Effectiveness of Insulin Pump Therapy in Children and Adolescents With Type 1 Diabetes. Diabetes Care 26:1142–1146, 2003 8. Jones TW, Davis EA. Hypoglycemia in children with type 1 diabetes: current issues and controversies. Pediatr Diabetes. 2003 Sep;4(3):143–50 9. Chase HP, Saib SZ, MacKenzie T, Hansen MM, Garg SK. Post–prandial glucose excursions following four methods of bolus insulin administration in subjects with type 1 diabetes. Diabet Med. 2002 Apr;19(4):317–21 10. Kaufman FR, Halvorson M, Kim C, Pitukcheewanont P. Use of insulin pump therapy at nighttime only for children 7–10 years of age with type 1 diabetes. Diabetes Care. 2000 May;23(5):579–82. 11. White NH, Hollander AS, Sadler M, Daniels I. Risks and benefits of continuous subcutaneous insulin infusion (CSII) therapy in children. Diabetes 2001;50: Suppl 2:A66 12. Celona–Jacobs N, Weinzimmer SA, Rearson M, Hartz D, Murphy k. Insulin pump therapy in children: a caution are tale. Diabetes 2001: Suppl 2:A67. 13. de Beaufort CE, Houtzagers CM, Bruining GJ, Aarsen RS, den Boer NC. Continuous subcutaneous insulin infusion (CSII) versus conventional injection therapy in newly diagnosed diabetic children: two–year follow–up of a randomized, prospective trial. Diabet Med. 1989 Dec;6(9):766–71 14. Weintrob N, Benzaquen H, Galatzer A, Shalitin S, Lazar L, Fayman G. Comparison of continuous subcutaneous insulin infusion and multiple daily regimen injections in children with type 1 diabetes: a randomized open crossover trial. Pediatrics. 2003 Sep;112(3 Pt 1):559–64 15. Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 2000 Dec;49(12):2142–8 16. Ahern JA, Ramchandani N, Cooper J, Himmel A, Silver D, Tamborlane WV. Using a primary nurse manager to implement DCCT recommendations in a large pediatric program. Diabetes Educ. 2000 Nov–Dec;26(6):990–4 17. Melki V, Renard E, Lassman–Vague V et al. Improvement of HbA1 c and Blood Glucose Stability in IDDM Patients Treated With Lispro Insulin Analog in External pumps. Diabetes care, 1998 Jun; 21 (6): 977–82 18. RENNER R, PF?TZNER A, TRAUTMANN M. Use of Insulin Lispro in Continuous Subcutaneous Insulin Infusion Treatment. Diabetes care, May 1999; 22(5):784–8

The use of biphasic insulin aspart in the treatment of patients with type 2 diabetes mellitus

Diabetes mellitus (DM) type 2 is one of the most common chronic diseases and is a non-infectious epidemic. Currently, about 200 million people in the world suffer from this disease. The number of people with diabetes increases annually by 5–7% and doubles every 15 years. DM is characterized by early disability and high mortality of patients due to late vascular complications. This circumstance places this disease among the socially significant. Among patients with this pathology, patients with type 2 diabetes account for more than 90%.

The pathophysiological disorders in type 2 diabetes are based on two main defects: insulin resistance and pancreatic β-cell dysfunction (impaired insulin secretion and relative insulin deficiency). These two disorders are very closely related and first lead to increased blood glucose levels after meals (postprandial glycemia - PPG), and subsequently to fasting hyperglycemia. In addition, the sensitivity of peripheral tissues to insulin decreases.

The International Diabetes Federation (IDF) has developed recommendations regulating therapeutic goals for type 2 diabetes (Table), based on which individual goals can be set to improve disease compensation.

Table. Therapeutic goals for type 2 diabetes mellitus

Strict glycemic control is of paramount importance to reduce the risk of micro- and macrovascular complications in type 2 diabetes. However, as the results of the UK Prospective Diabetes Study (UKPDS) show, as type 2 diabetes progresses, it becomes increasingly difficult to maintain optimal levels of fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) using only a hypocaloric diet and exercise. In this case, oral hypoglycemic drugs (OHDs) are prescribed. The main goal in the treatment of type 2 diabetes is to maintain blood sugar (glycemia) levels as close to normal as possible.

Currently, the following groups of PSSPs are used in the treatment of type 2 diabetes.

Drugs that enhance insulin secretion by the pancreas. This group of PSSPs includes sulfonylurea derivatives (PSM) - glibenclamide (Maninil), gliclazide (Diabeton MV), glimepiride (Amaril, Glemaz), gliquidone (Glyurenorm) and prandial glycemic regulators (glinides) - repaglinide (NovoNorm®). Each of the listed drugs has its own characteristics, mainly related to the duration of action. By increasing the stimulation of insulin by the pancreas, these drugs lower blood glucose levels.

Drugs that improve insulin sensitivity. This group of drugs includes biguanides and insulin sensitizers (thiazolidinediones). The main representative of the biguanide group is metformin (Glucophage, Siofor, Bagomet, Metfogamma). Metformin reduces the production of glucose by the liver by inhibiting gluconeogenesis and enhances the uptake of glucose by peripheral tissues without stimulating insulin secretion by the pancreas. Metformin is the drug of choice in the treatment of patients with type 2 diabetes and excess body weight. The drug is successfully used in combination with other PSSPs and insulin.

A subgroup of insulin sensitizers (thiazolidinediones) is represented by pioglitazone (Actos) and rosiglitazone (Avandia).

Drugs that reduce the absorption of carbohydrates in the intestines. This group includes acarbose (Glucobay), which is an inhibitor of α-glucosidases. Acarbose prevents the rise in blood glucose levels after meals by inhibiting the absorption of carbohydrates from food in the small intestine.

Combined drugs. They consist of several components, these include, for example, Glibomet (glibenclamide + metformin), Avandamet (rosiglitazone + metformin).

However, the effective action of many PSSPs occurs only when residual β-cell secretion is maintained. The progressive decline in β-cell function and insulin resistance characteristic of type 2 diabetes prevent the achievement of the desired effect even with combination therapy of several PSSPs. In this case, the best treatment option available is insulin therapy. One of the conclusions of the UKPDS study is: “We are not starting insulin therapy as early or as aggressively as needed” [2].

Maintaining the level of glycated hemoglobin within the recommended target values (< 7.0% - according to the recommendations of the American Diabetes Association; 6.5% - according to the recommendations of the International Diabetes Federation, the American Association of Clinical Endocrinology, the Ministry of Health and Social Development of the Russian Federation) reduces the risk of developing micro- and macrovascular complications of diabetes [5–8]. However, in recent years, there has been increasing evidence of the role of PPG as an independent risk factor for cardiovascular morbidity and mortality [9]. These data are very important in clinical practice, since patients with GKN levels close to target values may still have high levels of PPG [10, 11]. Indeed, it has been shown that when HbA1c < 7.3%, more than 70% of the total hyperglycemia is due to PPG [12]. Therefore, patients need to be prescribed more intensive treatment regimens aimed at controlling both GCH and PPG, educating them on the importance of targeted control of PPG and HbA1c levels [13]. Basal-bolus regimens with prandial administration of short-acting insulins and one or two injections of basal insulin are one of the possible options for intensifying insulin therapy to achieve recommended glycemic control goals. However, this option for starting insulin therapy is complicated due to the multiple injections required. In addition, basal-bolus therapy is not always indicated for patients in the early stages of type 2 diabetes with preserved residual β-cell function [14]. A single-dose regimen of basal insulin or a basal insulin analogue may also be an effective and practical option for starting insulin therapy when PSSP therapy alone no longer maintains satisfactory glycemic control [15, 16]. Although approximately 58% of patients on this regimen achieve a target HbA1c level of <7%, postprandial glycemic values may remain high [17, 18].

To improve the control of PPG while maintaining the BGN within the recommended values, insulin therapy using biphasic insulin analogues is optimal for patients with type 2 diabetes.

Biphasic insulin aspart (NovoMix® 30 - Novo Nordisk, Denmark) is a mixed dosage form containing 30% soluble and 70% protamine crystalline insulin aspart (Fig. 1). The first ultra-short-acting component reduces blood glucose levels after meals, and the second provides the basal (long-term) need for insulin. The combination of fast- and slow-acting components makes it possible to reproduce the profile of physiological insulin secretion. Therapy with NovoMix® 30 is indicated for patients with type 2 diabetes with unsatisfactory glycemic control while taking PSSP in sub- and maximum doses; with unsatisfactory control of PPG during therapy; in case of frequent, repeated hypoglycemia; patients who, for objective reasons, find it difficult to switch to intensive insulin therapy.

The potential benefits of using NovoMix®30 in patients with type 2 diabetes have been assessed in several international studies.

Figure 1. Daily glycemic profiles in groups 1 and 2 of patients initially and after 3.5 months during therapy with NovoMix 30

The ACTION (Achieving Control Through Insulin plus Oral agents) study compared intensification of PSSP therapy with insulin therapy in a two-injection regimen [32]. The study lasted 24 weeks. It included patients with type 2 diabetes who failed to achieve target HbA1c values during PSSP therapy.

At the end of the study, 76% of patients were able to achieve an HbA1c < 7% in the NovoMix® 30 + PSSP group compared to 24% of patients receiving PSSP therapy alone. More patients with type 2 diabetes and unsatisfactory control during therapy with two PSSPs were able to achieve the recommended target HbA1c levels during therapy with NovoMix® 30 in combination with metformin and pioglitazone.

The study by Kabadi & Kabadi [27] examined the possibility of improving glycemic control in patients with type 2 diabetes when they were prescribed NovoMix® 30 insulin as a single injection in combination with metformin, PSM or both PSPS. It included 46 men with type 2 diabetes aged 45–70 years with an HbA1c level > 7.5%. The duration of the study was 6 months. At baseline, patients received either metformin alone (2500 mg/day), or glimepiride only (8 mg/day), or a combination of these drugs (2500 mg/day + 8 mg/day).

During the study, patients continued to receive their previous PSSP therapy with the addition of NovoMix® 30 (n = 38). 8 patients were transferred to placebo + NovoMix® 30 therapy with the abolition of PSSP. At baseline, body weight and HbA1c levels did not differ significantly between groups.

After 6 months, patients in all groups showed a significant decrease in HbA1c, including patients receiving NovoMix® 30 + placebo. Control goals (HbA1c < 7%) were achieved by patients in all groups. There were no episodes of severe hypoglycemia in any group.

Thus, single-injection therapy with NovoMix® 30 insulin provided all groups with the opportunity to achieve the target value for HbA1c < 7.0% and fasting plasma glucose (FPG) 5–7.2 mmol/l. A lower dose of insulin was observed during combination therapy with NovoMix® 30 with metformin and PSM.

The PREFER study [33] compared the effectiveness of two promising insulin analog therapy regimens: NovoMix® 30 in two injections and basal-bolus therapy (Levemir® + NovoRapid®). The duration of the study was 26 weeks. It included 715 patients with type 2 diabetes with a level of 7% < HbA1c < 12%, who had previously received PSSP therapy alone (72%) or in combination with insulin glargine (Lantus) or NPH insulin.

Insulin therapy NovoMix® 30 (n = 178) began with two injections per day (0.2 U/kg before breakfast and 0.1 U/kg before dinner). Basal-bolus therapy (n = 537) began with one injection of Levemir® insulin (10 units or 14 units if BMI > 32 kg/m2) plus prandial NovoRapid® insulin. Doses were selected individually in a ratio of 3: 2: 1 (for breakfast, lunch and dinner, respectively). PSSPs were abolished in both treatment groups.

Both insulin analog therapy regimens provided the opportunity to safely achieve the target HbA1c level of 7.0%: 50% in the NovoMix® 30 insulin therapy group and 60% in the Levemir® and NovoRapid® insulin therapy group in patients with type 2 diabetes. Patients who had not previously received insulin therapy achieved equal glycemic control during therapy with a biphasic analogue and basal-bolus therapy.

The average GKN value also turned out to be the same: 8.05 mmol/l during therapy with NovoMix® 30 insulin and 8.27 mmol/l during basal-bolus therapy with insulin Levemir® and NovoRapid® (p = 0.345). The incidence of hypoglycemia was low and comparable for both insulin analog therapy regimens.

The aim of the randomized, open-label, parallel-group EuroMix study [24] was to compare the safety efficacy of two insulin analogue therapy regimens in 255 patients with type 2 diabetes: insulin NovoMix® 30 in a two-injection regimen in combination with metformin (n = 128) and insulin Lantus as a single injection in combination with glimepiride once a day (n = 127). The primary study parameter was the difference in the dynamics of HbA1c reduction between groups after 26 weeks of therapy.

Figure 2. Dynamics of prandial increase in glycemia initially and after 3.5 months during therapy with NovoMix 30

The study showed that starting insulin therapy with the use of the biphasic analogue NovoMix® 30 in a two-time regimen in combination with metformin provides a more pronounced decrease in HbA1c levels and the average prandial increase in glycemia in patients with type 2 diabetes compared to therapy with the insulin analogue Lantus® in a single injection regimen in combination with glimepiride.

We conducted a study in 10 administrative districts of Moscow to study the effectiveness of the drug NovoMix® 30 in everyday clinical practice for 3.5 months in 3,000 patients with type 2 diabetes with unsatisfactory glycemic levels during previous therapy.

For the final analysis, 309 questionnaires were selected by random sampling (every 10th questionnaire). The duration of type 2 diabetes was 11.5 ± 1.5 years. Before transferring to NovoMix® 30, patients received monotherapy with PSSP or combination therapy with PSSP and insulin. The HbA1c level in the total group of patients was initially 9.3 ± 1.5%. During the study, patients were divided into two groups: in the 1st group, patients received NovoMix® 30 in two injections in combination with PSSP, in the 2nd group - NovoMix® 30 in three injections without PSSP.

Figure 3. Dynamics of prandial increase in glycemia initially and after 3.5 months during therapy with NovoMix® 30

Group 1 consisted of 250 patients (195 women/55 men), the average duration of the disease was 11.5 ± 6.2 years, the initial HbA1c level was 9.3 ± 1.8%, FCL 9.9 ± 2.3 mmol/ l, PPG 11.7 ± 2.7 mmol/l. This group received NovoMix® 30 in two injections before breakfast and before dinner in combination with PSSP, represented by sulfonylurea drugs and metformin in maximum doses.

Group 2 included 59 patients (44 women/15 men), with an average disease duration of 11.7 ± 7.8 years, initial HbA1c levels of 9.4 ± 1.8%, FCL 9.5 ± 2.5 mmol/l, PPG 11.3 ± 2.6 mmol/l. This group of patients received NovoMix® 30 in a regimen of three injections before main meals.

The analysis data showed that during observation in both groups, the daily glycemic profile (8 points), determined during self-monitoring (p < 0.02) (Fig. 1, 2), and HbA1c significantly improved.

There was a significant decrease in the average prandial increase in glycemia (average increase in glycemia from preprandial at 90 minutes after a meal; p < 0.04) in comparison with the initial values (p < 0.01) in both groups of patients (Fig. 3).

Figure 4. Dynamics of HbA1c at baseline and after 3.5 months during therapy with NovoMix® 30

By the end of the study, in both groups of patients, the HbA1c level decreased to 7.5 ± 0.8% (Fig. 4).

Thus, data on the use of the biphasic insulin analogue NovoMix® 30 in the treatment of patients with type 2 diabetes allow us to draw the following conclusions.

Starting therapy with one injection of NovoMix® 30 in addition to PSSP makes it possible to effectively achieve target disease control.
Intensification of NovoMix® 30 therapy to two or three injections allows achieving the target level in most patients without increasing the risk of hypoglycemia.
Control of PPG and improvement of the lipid profile during therapy with the biphasic analogue NovoMix® 30 may potentially reduce the risk of cardiovascular complications.
Control of PPG is an important component of diabetes management.
Insulin therapy must not only be started in a timely manner, but also intensified in a timely manner.

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M. B. Antsiferov , Doctor of Medical Sciences, Professor L. G. Dorofeeva Endocrinological Dispensary of the Moscow Department of Health

The “Insulin Era” began a little less than a hundred years ago, when in August 1921 the discovery of the Romanian scientist N. Paulescu was reported. He was the first to obtain an aqueous extract from the pancreas of dogs and cattle, when administered into the blood of animals, a decrease in glycemia, glucosuria, and even the development of hypoglycemia was noted. The first use of insulin to reduce glycemia in humans was in 1922. An extract from the pancreas of cattle was used, obtained by C. Best and F. Banting and prepared using a special technology developed by J. Collip. Since this period of time, natural insulin preparations have been used in the treatment of diabetes mellitus (DM). In 1936, in laboratories (Denmark) prof. H.S. Hagedorn was the first in the world to create neutral insulin with an intermediate duration of action. “Neutral insulin Hagedorn” became the prototype of protafan. The “first” insulin preparations made it possible to prolong the life of patients suffering from diabetes, but had quite a lot of side effects and could not maintain a normal glycemic level for a whole day. In 1946, the first long-acting neutral insulin, isophane insulin (NPH), was developed, but its duration of action was insufficient. Research continued, and in 1951, developments appeared to prolong the action of insulin with the help of zinc. Thus, in 1953, the use of extended-release zinc insulin suspension began. However, these were still insulins based on a “foreign” protein, which increased the number and frequency of side effects. In 1953, Sanger deciphered the chemical structure of insulin, which made it possible to improve the quality of insulin preparations used. The time has begun for active scientific research to solve the problem of high purification of the hormone. High-performance chromatography made it possible to obtain monocomponent insulins, practically free of additional impurities. This technology has made it possible to get rid of many adverse reactions during insulin therapy, delay the development of late complications of diabetes and set new standards for the degree of purification of insulin. But, in reality, the era of the pharmacological “race” for the best insulin drug began only in 1977 with the discovery of the structure of DNA 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 resulting products, which in turn led to the emergence in pharmacology of a new direction in the synthesis of new molecules with improved properties of previously studied substances and drugs. In 1981, recombinant human insulin was produced for the first time in the world. Thus ended the era of insulins of animal origin; genetically engineered insulins, absolutely identical to the one produced by the human pancreas, began to be used to correct glycemia. They are obtained through a complex biotechnological “rearrangement” of the DNA of ordinary baker’s yeast, a product used by humanity for thousands of years. Over time, it turned out that, despite the “absolute identity,” human genetically engineered insulins differed from their own insulin in pharmacodynamics and pharmacokinetics. Long-acting insulins have peaks of action, which increases the risk of developing hypoglycemic conditions. Short-acting insulins have a maximum activity of action, which does not allow persistent postprandial normoglycemia, and the onset of action is quite delayed from the moment of drug administration, which is inconvenient for patients. Work on improving the properties of insulins continued. And in 1999, the first short-acting insulin analogue appeared - NovoRapid, and a little later the long-acting insulin Detemir. Compared to long-acting human insulins (LAH), long-acting insulin analogues have a longer duration of action, no peak of action and, as a result, a reduced risk of hypoglycemia. The particular advantages of long-acting insulin Detemir include low intra-individual variability and less weight gain, with an equal or even superior glucose-lowering effect to NPH. Thus, starting from the last century, the pharmacological market for insulin preparations has changed significantly - from bovine and porcine insulins through human genetically engineered insulins to analogue insulins. Insulin preparations currently used differ mainly in four main ways: by origin; by the speed of onset of effects and its duration; according to the method of purification and the degree of purity of the drugs, as well as the concentration and percentage of insulin. Not so long ago, mixed insulins entered the practice of doctors, i.e. combined in one solution both short-acting insulin and a long-acting form of insulin. This article will focus on the use of just such insulin analogues.

Diabetes is a chronic disease with steady progressive growth. The number of patients with both type 1 diabetes and type 2 diabetes increases every year. It is not without reason that diabetes is called an “epidemic and pandemic.” It is expected that by 2030 the total number of people with diabetes will increase to 438 million people, i.e. Every 19th person on the planet will suffer from it. The number of patients with diabetes in the Russian Federation is about 9 million; in the last 10 years alone it has doubled [1]. According to the Ministry of Health and Social Development of Russia, in 2000, 162 thousand people suffered from diabetes, and in 2009 this figure increased to 308.6 thousand people [incidence of the population with socially significant diseases (patients with a diagnosis established for the first time in their lives are registered) data from the Ministry of Health and Social Development of Russia , Rosstat calculation]. According to WHO forecasts, by 2030 there will be 13.8 million patients with diabetes in Russia. The severity of the disease is determined by its complications, which also lead to the death of patients. According to statistics, every 6-7 patients out of 10 die from macroangiopathic complications of diabetes. Moreover, along with the prevalence of diabetes, socio-economic losses associated with the development of severe disabling complications are also increasing. It has been noted that 20 years after the diagnosis of diabetes, approximately 2/3 of patients develop retinopathy, and 30% develop nephropathy during the rest of their lives [2, 3]. It is recognized throughout the world that normalizing glycemic levels helps reduce the rate of development and severity of diabetic complications.

Representative studies (UKPDS, Steno-2, DCCT/EDIC) prove that normalizing glycemic levels in diabetes reduces the risk of developing micro- and macrovascular complications [4-6]. In this regard, national and international organizations have established target glycemic levels, the achievement of which is the primary goal of patients and doctors. To reduce the risk of microvascular and macrovascular complications, the target HbA1c level varies slightly between countries (ADA/EASD, 2009), but should not exceed 7% [7, 8].

The pathognomonic treatment of type 1 diabetes is constant insulin replacement therapy, since the leading mechanism for the development of type 1 diabetes is autoimmune damage to β-cells, followed by their destruction and the development of absolute insulin deficiency. The creation of analogue insulins with properties as close as possible to the physiological needs of humans has significantly improved the quality of life of our patients.

Currently, two main theories of the pathogenesis of type 2 diabetes are considered: decreased sensitivity of peripheral insulin-dependent tissues to the action of insulin or insulin resistance (IR) and insufficient (inadequate) insulin secretion. In recent years, it has been proven that IR is a genetically determined process, which worsens as obesity progresses. That is why much attention is paid to controlling body weight during insulin therapy, because insulin is the main hormone that promotes an increase in fat mass. The inability of the pancreatic insular apparatus to adequately produce insulin to overcome IR develops gradually. According to laboratory studies, patients first develop insufficiency, and later the absence of the 1st phase of insulin secretion, the physiological role of which is to regulate post-alimentary hyperglycemia. A so-called “vicious circle” is formed: a decrease in the sensitivity of peripheral tissues to insulin, on the one hand, stimulates its secretion, and on the other, due to the increase in postprandial hyperglycemia, the phenomenon of “glucotoxicity” appears, leading to a decrease in the secretory capabilities of β-cells. When type 2 diabetes manifests itself, on average, insulin secretion decreases by 50%, continuing to decline by 4-6% per year [9], and 10 years after the onset of type 2 diabetes, insulin secretory function decreases in 50-60% of patients β-cells of the pancreas are more than 75% of normal values, which leads to the need for insulin replacement therapy [6, 10]. Hyperinsulinism, aimed at overcoming hyperglycemia, leads to an increase in appetite, consequently, to an increase in body weight, which aggravates IR and increases the need for insulin secretion. Short courses of insulin therapy are indicated for patients with type 2 diabetes who have normal body weight, taking into account the positive effect of this therapy on the functional state of the islet apparatus of the pancreas. Recently, insulin therapy has been increasingly used in the treatment of patients with type 2 diabetes to achieve compensation for carbohydrate metabolism and reduce complications of diabetes. This type of therapy for type 2 diabetes in the USA is approximately 40%, in Russia 5 years ago it was only 10%, currently more than 20% of patients in the Russian Federation with type 2 diabetes are on insulin therapy.

When is it necessary to prescribe insulin therapy to patients with type 2 diabetes? The answer to this question is provided by one of the conclusions of the UKPDS study, which states: “We are not starting insulin therapy as early and as aggressively as necessary” [10]. Fear of starting insulin therapy due to the possible development of hypoglycemic conditions, weight gain, etc. leads to the formation of severe complications in fairly young people of working age. The use of insulin therapy allows adequate control of not only fasting glucose (FG), but also postprandial glycemia (PPG). It is PPG that leads to an increased risk of cardiovascular complications [11] and makes a significant contribution to elevated HbA1c levels [12, 13]. The use of biphasic insulin analogues makes it possible to achieve improved control of PPG while maintaining BGN within the recommended values in patients with type 2 diabetes when it is impossible to achieve normoglycemia during PSSP therapy.

Let us consider the distinctive features of the modern biphasic analogue insulin NovoMix 30. It should be noted that aspart, the main component of this insulin, has in vitro

proven safety data identical to the safety data for human insulin [14, 15]. NovoMix 30 is a suspension of 30% soluble insulin aspart and 70% protamine crystallized insulin aspart. The pharmacokinetic properties of the insulin analogue aspart ensure active absorption of the soluble component, rapid onset of its action and rapid elimination from the body [16]. It is these features of NovoMix 30 that contribute to optimal control of PPG in patients with type 2 diabetes. At the same time, the slower absorption of the protaminated component provides the basal component of insulin therapy and has the same absorption profile as NPH insulin [17] (Fig. 1).

Figure 1. Diagram of the action profile of biphasic human insulin, biphasic insulin analogue, intermediate-acting insulin (ILA), and endogenous insulin as a function of food intake and timing of insulin injection.
Optimized modern insulin therapy involves matching plasma insulin levels to blood glucose levels that fluctuate with food intake. After a meal, when the glycemic level increases, a corresponding peak of insulinemia is required. In this situation, the rapid component of insulin NovoMix 30, aspart, makes it possible to match the peaks of postprandial glycemia and insulinemia, which makes it possible to improve the control of PPG in comparison with short-acting human insulin. Rapid elimination of the action of insulin aspart, compared with the delayed elimination of PI, minimizes the risk of late postprandial hypoglycemia.

Although the drug is a biphasic insulin, its action profile is characterized by a single peak, which makes it possible to reproduce the profile of physiological insulin secretion. A comparison of the pharmacodynamics and pharmacokinetics of NovoMix 30 and basal-bolus therapy with insulins glargine and glulisine was carried out in 2009 by a group of scientists led by T. Heise. As a result of the study, it was proven that biphasic analogue insulin aspart has a profile that coincides with basal-bolus therapy [18]. This biphasic insulin analogue can be used either as monotherapy or in combination with PSSP.

Several treatment regimens with NovoMix 30 insulin have been developed. It can be used from one to three times a day [19] (Fig. 2).

Figure 2. NovoMix 30: initiation and intensification of insulin therapy (adapted from Garber et al. [19]). The optimal starting dose of the drug is 1 injection before dinner at a dose of 12 units. At the same time, the patient continues to follow the diet, physical activity, taking PSSP (with the abolition of secretagogues before dinner), we recommend leaving the dose of metformin the same.

J. Garber et al. obtained the following results: with a single injection regimen, 41% of patients achieved control goals according to ADA recommendations (HbA1c <7%), and 21% of patients achieved more ambitious glycemic control goals according to AACE and IDF recommendations (HbA1c ≤6.5%). In the two-injection regimen of NovoMix 30 therapy, these same control goals were achieved by 70 and 52% of patients, respectively. During NovoMix 30 therapy with three injections per day, 60% of patients were able to achieve target HbA1c values of ≤6.5% and 77% of patients achieved HbA1c levels of <7.0%.

The study by Kabadi & Kabadi [20] examined the possibility of improving glycemic control in patients with type 2 diabetes when prescribing NovoMix 30 insulin as a single injection in combination with metformin, a sulfonylurea drug (SMU) or both SUDs. As a result of the study, it was found that therapy with insulin NovoMix 30 in a single injection mode allowed all groups to achieve the target value for HbA1c < 7.0% and fasting plasma glucose (FPG) 5-7.2 mmol/l. In addition, it was noted that the minimum dose of NovoMix 30 required to achieve stable normoglycemia was in the group of combination therapy with the drug with metformin and PSM.

The most common scheme in practical healthcare is the double administration of NovoMix 30 with the additional use of PSSP.

The ACTION (Achieving Control Through Insulin plus Oral agents) study showed that 76% of patients were able to achieve HbA1c < 7% in the group using the combination of NovoMix 30 + PSSP compared to 24% of patients receiving PSSP therapy alone [21].

P. Kann et al. [22] conducted work to compare the effectiveness and safety of using two different regimens for initiating insulin therapy in patients with type 2 diabetes NovoMix 30 + metformin and glargine + glimepiride. As a result, it was noted that 33.1% of patients from group 1 achieved the target HbA1c ≤ 7% compared to 26.2% in group 2. The average prandial gain (on average after three meals) was also significantly lower in the NovoMix 30 + metformin treatment group (–1.2 mmol/l). An increase in body weight was noted in both groups, but in the 1st group it was 0.7 kg, and in the 2nd group - 1.5 kg, which was significantly greater.

Also worthy of attention is the OnceMix study, which is devoted to a comparative assessment of the results of using therapy with a single injection of NovoMix 30 insulin or insulin glargine against the background of preserved PSSP therapy (metformin and glimepiride) in poorly compensated patients with type 2 diabetes. Patients of group 1 had a significantly better PPG level. In both groups, there was an improvement in glycemic control and a decrease in HbA1c levels, but by the end of the study in the group using NovoMix 30, it was 7.1% compared to the glargine group - 7.3% (p < 0.05). A slightly higher risk of developing nocturnal hypoglycemic episodes was noted in patients of group 1, however, the total number of hypoglycemic states during the day was the same in both treatment groups [23].

One of the interesting studies compared the effectiveness and safety of the use of the biphasic analogue NovoMix 30 in a two-time regimen in combination with metformin and the analogue insulin glargine in a single injection regimen in combination with glimepiride. This was a randomized, open-label, parallel-group study of EuroMix, which included 255 patients with type 2 diabetes poorly controlled on PSSP for 26 weeks. As a result of the study, it was revealed that the start of insulin therapy using the biphasic analogue NovoMix 30 in a two-fold regimen in combination with metformin provides a more pronounced decrease in HbA1c levels and the average prandial increase in glycemia in patients with type 2 diabetes in comparison with therapy with the insulin analogue glargine in a single regimen injections in combination with glimepiride. It should be especially noted that ADRs were recorded in 7.8% of patients using NovoMix 30 insulin, versus 8.7% in the insulin glargine group [22].

One of the most large-scale studies of patients with type 2 diabetes in the world in general and in Russia in particular is the IMPROVE study evaluating the use of NovoMix 30 in routine clinical practice [24]. The Russian part of the study involved 4869 patients; the observation period was 26 weeks. Participants included individuals who had not previously received SST; patients who were on PSSP therapy; patients on insulin therapy ± PSSP. The data obtained confirmed the high effectiveness of NovoMix 30 insulin when starting insulin therapy or when switching to NovoMix 30 insulin therapy from other types of insulin, combined with an extremely low amount of SNR - 6 (<0.1%). When assessing the level of glycemic control (based on HbA1c, FPG, PPG levels), a significant improvement was revealed with a maximum effect at the end of the study when switching to NovoMix 30. As in a number of other studies [19, 25, 26], the best results were demonstrated in the group of patients who have not previously received any treatment for diabetes. Thus, HbA1c levels <7.0% were achieved by 54% of patients who had not previously been treated, 42% who had previously received PSSP therapy, and 37% who had previously been on insulin ± PSSP therapy.

Conclusion

Insulin therapy in patients with type 2 diabetes should be started as early as necessary - when the HbA1c level is more than 7% in patients who are on a diet and are on therapy with maximum doses of PSSP.

It is important to remember that in a patient with newly diagnosed type 2 diabetes, the effectiveness of insulin therapy is higher with minimal doses of the drug used.

Early and stable compensation of type 2 diabetes reduces the number of complications and the rate of their development, and provides a higher level of quality of life for the patient. Insulin is not a death sentence, but a way to avoid disability against the background of developing diabetic complications and early death.

Insulin, being an anabolic hormone, promotes weight gain. When prescribing insulin therapy, it is necessary to continue to adhere to the principles of rational nutrition and adequate physical activity. It should be remembered that analogue insulins have minimal effect on body weight.

Modern analog insulins allow you to lead an active lifestyle and can be combined with PSSP therapy, with injections administered at the optimal time to maintain normoglycemia.

Insulin NovoMix 30, having both long and short insulin components, allows adequate control of both FPG and PPG.

Biphasic analog insulin NovoMix 30 can be prescribed to patients 1 to 3 times a day, depending on the needs and goals of glycemic control, under glycemic control.

It is very important to remember that insulin therapy must not only be started in a timely manner, but also intensified in a timely manner.

Treatment that brings results increases the patient's trust in the doctor and adherence to therapy!

Publications in the media

A group of scientists led by Nadezhda Balabushevich is creating insulin-containing microparticles that are resistant to digestion. They tested several variants of such particles on animals.

The need to take daily injections of the hormone insulin causes certain inconvenience to people suffering from hormone-dependent diabetes mellitus. It would be much more convenient to take insulin in tablet form. Those don't exist yet. However, perhaps they may soon appear thanks to the work of chemists from M.V. Lomonosov Moscow State University. Scientists have created a special form of insulin that works effectively when taken orally. This is confirmed by animal experiments.

Diabetes mellitus is a common disease of the endocrine system, in which the pancreas secretes insufficient amounts of the hormone insulin, or the body's cells are insensitive to it. If little insulin is produced, the patient becomes dependent on daily injections of this hormone. Constant injections are not very convenient, not entirely simple and hardly pleasant. Researchers from the Faculty of Chemistry of Moscow State University are solving the problem. M. V. Lomonosov. They are developing a microencapsulated form of the hormone that can be fully effective when taken orally, that is, in the form of a tablet.

Attempts to create non-injectable forms of insulin have been made in the scientific world for a long time. Insulin aerosols have already been released in inhalers, but they are quite expensive, cannot completely replace injections and have many contraindications. It has not yet been possible to make a tablet of the hormone, since gastric juice and enzymes of the gastrointestinal tract would break it down into completely useless components. A group of scientists led by Nadezhda Balabushevich is creating insulin-containing microparticles that are resistant to digestion. They tested several variants of such particles on animals. They were administered subcutaneously to rabbits, and orally to rats, and in both cases the hormone was properly absorbed by the body. Scientists suggest that tablets that can be created based on their development could be a good alternative to injectable forms of insulin.

Specialists from the Department of Chemical Enzymology, Faculty of Chemistry, Moscow State University, have developed polyelectrolyte complex microparticles for oral delivery of insulin to the patient’s body. Researchers have come up with a method that makes it possible to obtain particles with a high content of the hormone - at least 50%. Microparticles with a size of 3-10 microns are stable in the acidic environment of the stomach, and are not digested by enzymes of the gastrointestinal tract (pepsin, trypsin, chymotrypsin) due to the action of chitosan and aprotinin. The protein molecules of insulin are quite large, but the mucoadhesive properties of the microparticles allow the membranes of epithelial cells to easily pass them into the blood.

Researchers administered a microencapsulated form of the hormone to healthy rabbits, and it fully retained its biological activity. And when the microparticles were orally administered to diabetic rats, an effect almost identical to that of injected insulin could be observed.

Nadezhda Balabushevich, head of the study, comments: “More than two thousand scientific studies have already been carried out around the world on the study of alternative insulin delivery systems. The most convenient method for use by diabetics would be the oral method of administering the hormone. This is difficult for proteins. Our laboratory is developing new insulin-containing microparticles that demonstrate a high yield of bioavailable hormone when administered orally. In order to prove the possibility of this form of insulin to become a replacement for injections, numerous preclinical trials are required.”

Insulin Humalog Quick Pen syringe pen 100IU/ml 3ml N5 (Eli Lilly)

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in potency, brand (manufacturer), type (eg, Regular, NPH, Lente), species (animal, human, human insulin analog), and/or production method (DNA recombinant insulin or animal insulin) may result in the need dose changes. Conditions in which early warning symptoms of hypoglycemia may be nonspecific and less severe include long-term diabetes mellitus, intensive insulin therapy, nervous system disease associated with diabetes mellitus, or use of medications such as beta-blockers. In patients with hypoglycemic reactions after switching from animal insulin to human insulin, early symptoms of hypoglycemia may be less severe or different from those they experienced with their previous insulin. Uncorrected hypoglycemic or hyperglycemic reactions can cause loss of consciousness, coma, or death. Use in inadequate doses or discontinuation of treatment, especially in insulin-dependent diabetes mellitus, can lead to hyperglycemia and diabetic ketoacidosis, conditions that are potentially life-threatening to the patient. Insulin requirements may be reduced in patients with renal failure, as well as in patients with liver failure, as a result of decreased gluconeogenesis and insulin metabolism. However, in patients with chronic liver failure, increased insulin resistance may lead to increased insulin requirements. The need for insulin may increase with infectious diseases, emotional stress, and with an increase in the amount of carbohydrates in the diet. Dose adjustment may also be required if the patient increases physical activity or changes the usual diet. Exercise immediately after eating increases the risk of hypoglycemia. A consequence of the pharmacodynamics of rapid-acting insulin analogs is that if hypoglycemia occurs, it may occur sooner after injection than with injection of soluble human insulin. The patient should be warned that if the doctor has prescribed an insulin drug with a concentration of 40 IU/ml in a vial, then insulin should not be drawn from a cartridge with an insulin concentration of 100 IU/ml using a syringe for administering insulin with a concentration of 40 IU/ml. If it is necessary to take other medications simultaneously with the drug