Про діабет

Use of recombinant human insulin preparations and insulin analogues in patients with type 2 diabetes

In the systematic review "Comparative Efficacy and Safety of Ready-Made AI Mixtures in T2DM", 16 studies were analyzed that compared ready-made AI mixtures with ready-made RIL mixtures. A generalized analysis showed that ready-to-use AI mixtures provide the same HbA1c control as ready-made RIL mixtures and the same fasting plasma glucose control as ready-made RIL formulas. AI mixtures were more effective than RIL mixtures in reducing postprandial glycemia (PPH). Ready-made AI mixtures can cause the same incidence of hypoglycaemia as ready-made RIL mixtures. The conclusion of the study is that ready-made AI mixtures provide glycemic control similar to that provided by ready-made RIL mixtures and may provide better glycemic control compared to the use of long-acting AI in combination with oral hypoglycemic drugs, however, data on clinical outcomes are very limited.

The PROGENS Benefi t observational study, aimed at comparing the efficacy, safety, and quality of treatment of patients with T2DM with ready-made RIL mixtures and ready-made AI mixtures, showed that both ready-made AI and RIL mixtures were effective and safe, and the patients examined were satisfied with both treatments. According to another study, comparing the efficacy and safety of the finished RIL mixture (Geninsulin M30) and the finished AI Aspart 30/70 mixture (NovoMix 30) in patients with T2DM, the levels of fasting glycemia, postprandial glycemia and HbA1c did not differ significantly in different patient groups. The number of cases of severe and mild hypoglycaemia also did not differ significantly between the compared groups of patients. Treatment with ready-made mixtures of Geninsulin M30 or NovoMix 30 for 6 months resulted in the same level of metabolic control of patients (fasting glycaemia, postprandial glycemia and HbA1c).

Ready-made mixtures of RIL (Geninsulin M30) and AI (NovoMix 30) showed the same safety profile. According to another review comparing insulin (RIL or animal-derived insulins) with AI, the differences between IA and RIL in terms of metabolic control remain very small (i.e., 0.09%) and are not clinically significant differences. Therefore, the available evidence suggests that AIs do not have an advantage over RIL in terms of metabolic control. When it comes to cases of hypoglycemia, AIs appear to have statistically significant advantages over RILs, but these benefits are not the same for different types of insulin (ultra-short or long-acting) or types of diabetes, and the clinical significance of these differences is not clear. In addition, many studies that have demonstrated a difference between AI and RIL in terms of the occurrence of hypoglycaemia have excluded patients with a history of recurrent cases of severe hypoglycaemia, so it may not be appropriate to assume that such benefits will be observed in all patients.

Another systematic review and meta-analysis included eight studies comparing the effects of long-acting AI and RIL in patients with T2DM. Six studies examined the AI Glargine and two examined Detemir. There was no HbA1c-lowering benefit for glargine. For Detemir, the meta-analysis showed a statistically significant but clinically insignificant advantage of RIL relative to metabolic control. The incidence of symptomatic and nocturnal hypoglycaemic events was lower in patients treated with AI Glargine than in patients treated with RIL. In addition, for Detemir, two studies showed that fewer patients experienced general or nocturnal hypoglycemic episodes in the Detemir treatment groups. The methodological quality of the included studies allows the results to be interpreted with caution.

To date, no studies have been conducted to investigate the possible long-term effects of AI. Therefore, it remains unclear whether and to what extent treatment with long-term exposure to AI will affect the development and progression of micro- and macrovascular events compared to the results obtained with RIL treatment. Because differences in overall effects on metabolic control were negligible for AI Glargine and RLI, and were even absent for AI Detemir, no significant improvement in the development of late microvascular complications is expected from long-acting AI treatment. As for the benefits of developing severe hypoglycemic conditions, they should be treated with some caution. No statistically significant benefit was found in the treatment of AI Glargine or Detemir. In addition, the interpretation of the results of the incidence of severe hypoglycemia is difficult due to the subjectivity of the complaints.

Patients may inappropriately deny severe hypoglycaemia and describe it as mild or moderate. More reliable definitions, such as "another person's injection of glucose or glucagon," may lead to more reliable data. In all studies, the incidence of severe hypoglycaemia was very low, making a clinical response from different insulin regimens unlikely. Although a meta-analysis found a consistent reduction in hypoglycaemia symptoms with the use of long-acting AI therapy, no reliable conclusions can be drawn from these results because the determination of hypoglycemia according to the symptoms described makes the results highly subjective, especially in open-label studies with (probably) a lack of assessment of blinded results. The advantage of AI Glargine and Detemir may be the reduction of nocturnal hypoglycemia in patients with T2DM compared to treatment with basal insulin.

No study has presented results  about the quality of life. One study reported data on treatment satisfaction and greater treatment satisfaction in patients treated with Glargine AI. Interpreting the clinical significance of this result is complicated by the fact that the initial and final values of the study are indicated, although the researchers claim a statistically significant improvement in the change in treatment satisfaction. In addition, the report was not presented at the appropriate level, and therefore it was not possible to assess the quality of this result. A comparison of ultra-short-acting AI with RLI was made in the Cochrane Review. The primary objective of this systematic review was to evaluate the impact of ultra-short-acting AI compared to RLI in patients with T1DM and T2DM. According to the review, no statistically significant differences in long-term metabolic control (HbA1c) between ultra-short-acting AIs compared to RLIs in T2DM; There were also no statistically significant differences in the incidence of hypoglycemic episodes between ultra-short-acting AIs compared to RLIs in patients with T2DM: Three studies (one double-blind, two open-label) found no significant differences between AIs and RLIs; 4 studies noted improvements in patient satisfaction with treatment in the AI group (mainly due to changes in convenience, flexibility and continuation of treatment, as well as the interval between injections and meals). In conclusion, a systemic review shows only a slight clinical benefit of ultra-short-acting AI in the majority of patients treated with insulin. Another study compared AIs and RLIs (long-acting AIs and NPH insulins, and ready-made AI mixtures with ready-made RLI mixtures) in patients with T1DM and T2DM and women with gestational diabetes. The aim of the study was to determine the benefits of glycemic control and the possibility of reducing the risk of complications and side effects.

A systematic review of randomized clinical trials was conducted. The results showed that the differences in HbA1c levels and the number of cases of hypoglycemia are small and cannot be considered clinically significant. According to the study authors, AI has no advantage in terms of glycemic control, but may be useful in treating patients with recurrent episodes of hypoglycemia to optimize existing treatment with RLI. Routine use of long-acting AI in T2DM is not recommended due to the high price/performance ratio. Ultra-short-acting AIs differ significantly in pharmacokinetics and pharmacodynamics compared to RLIs. Based on these results, it is widely believed that RLIs should be administered 20 to 30 minutes before meals to reduce postprandial glycemia levels compared to AIs administered just before meals. At the same time, the interval between injections and food intake for patients with T2DM is not mandatory.

Systematic review of 28 studies (10 for T2DM)  showed that short-acting RLIs and ultra-short-acting AIs (aspart) helped to achieve identical glycaemic control in T2DM, and that the same results were obtained when assessing HbA1c values and cases of hypoglycemia, including the risk of severe hypoglycaemia. In this case, short-acting RLIs showed better results for fasting glycemic control, and ultra-short-acting AIs (Aspart) showed better results for postprandial glycemic control. Another study conducted in Germany found that the long-term benefits of using long-acting AI for T1DM as a whole have not been adequately studied, and there is no evidence of the benefits of AI Glargine and Detemir compared to NPH insulin. Study of the use of long-acting AI in T2DM  did not show an advantage of AI Glargine and Detemir compared to NPH insulin in patients who did not receive intensive insulin therapy; in patients receiving intensive insulin therapy, basal AIs in combination with oral hypoglycemic drugs also did not show an advantage of IA Glargine and Detemir compared to NPH insulin, provided that RLI therapy was optimized. It was noted that in general  the long-term benefits of using long-acting AI in terms of influencing the development of late complications of diabetes mellitus are not well understood. Study of the use of ultra-short-acting AI in T1DM  showed that the benefits of aspart compared to RLI in adult patients are not evident due to a lack of data; in patients at higher risk of hypoglycaemia, the same result has been demonstrated with the use of the ultra-short-acting AIs Lispro and RLI, and the benefits of Lispro in patients at increased risk of severe hypoglycemia are not clear.

Another analysis shows little clinical benefit of long-acting AI treatment for patients with T2DM treated with long-acting AI as "basal" insulin for symptomatic nocturnal hypoglycemic events. "Until long-term efficacy and safety data are available, we propose a cautious approach to therapy with Glargine or Detemir," the findings said. 

My Diabetes Solutions

M.V. Neborachko, O.G. Phakadze