RU2491925C2 - Method for prediction of clinical effectiveness of diabetic polyneuropathy in patients with type 2 diabetes mellitus and dyslipidemia - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely endocrinology, and concerns predicting the clinical effectiveness in diabetic polyneuropathy in the patients suffering type 2 diabetes and dyslipidemia. That is ensured by evaluating the intensity of diabetic polyneuropathy manifestations taking into account neuropathic dysfunctional score, evaluating triglycerides and glycolised blood hemoglobin before the treatment; the derived data are used to specify a therapeutic approach followed by further estimation of a probability of a successful correction of diabetic polyneuropathy by formula $$P=1-\frac{1}{1+e^{-(0,99-1,78\cdot Z)}},$$

wherein e is the basis of hyperbolic logarithm e=2.72; Z is a regression coefficient calculated by formula 7=4.56-0.05*"ДлСД"-0.02*IntDPN-0.05*TG-0.53*HbAlc+0.14TherApp; if the value P is 0.7 or more, the successful correction of DPN is predicted in the patients, and the value P less than 0.7 requires the therapeutic approach to be changed.

EFFECT: method provides the improved clinical effectiveness ensured by the individual therapeutic approach based on the lipid and carbohydrate metabolism of a specific patient.

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Description

The invention relates to medicine, namely to endocrinology and diabetology and can be used to predict the effectiveness of treatment of diabetic polyneuropathy according to the results of a study of the initial parameters of carbohydrate and lipid metabolism, the severity of polyneuropathy and the use of various schemes of hypoglycemic and hypolipidemic drugs.

Diabetic polyneuropathy (DPN) is one of the frequent and serious complications of diabetes mellitus (DM). With type 2 diabetes lasting more than 25 years, DPN is detected in more than 50% of patients (Kempler P. Diabetic neuropathy: clinical problems and possible treatment approaches. // Complications of diabetes mellitus: pathophysiology and options for pathogenetic treatment. Edited by P.J. Tornelli and P. Kemplera, International Workshop of Experts, Rome (Italy), 2008 - P.36-45). Recently obtained evidence that DPN occurs in 13% of cases among patients with impaired glucose tolerance and in 11.3% with elevated fasting plasma glucose (Ziegler D, Rathmann W, et al. Prevalence of Polyneuropathy in Prediabetes and Diabetes is Associated with Abdominal Obesity and Macroangiopathy. The MONICA / KORA Augsburg Surveys S2 and S3 // Diabetes Care. - 2008. - Vol.31. - P.464-469) indicate that DPN is not only one of the most common complications of type 2 diabetes, but can also develop much earlier than the clinical manifestation of this disease. In this regard, only disorders of carbohydrate metabolism cannot explain both the development and progression of DPN. In a 2009 study by Wiggin T.D. et al. an association of elevated triglycerides with the progression of diabetic polyneuropathy (Wiggin TD, Sullivan KA, Pop-Busui R., Amato A., Sima AA, Feldman EL Elevated Triglycerides Correlate with Progression of Diabetic Neuropathy. // Diabetes published online. May 1. - 2009 .-- as db08-1771). According to the authors, the correlation between triglycerides and the progression of diabetic neuropathy suggests that hyperglycemia and impaired glucose metabolism are not the only factors contributing to nerve damage, and the nature of lipid metabolism disorders must be taken into account.

A known method for the treatment of diabetic polyneuropathy (RF patent No. 2191011, publ. 20.10.2002), which consists in the fact that after achieving compensation for diabetes mellitus with the help of insulin therapy and / or hypoglycemic drugs, thyroid hormones are additionally prescribed to patients in a dose of 12.5 to 50 μg . The use of thyroid hormones in the method of treating DPN leads to an increase in the rate of propagation of excitation in n. tibialis, n. peroneus, n. suralis, determined by electroneuromyography, and hence the improvement of vibrational, tactile, temperature sensitivity both in patients with diabetes mellitus with thyroid disease and in patients with diabetes without thyroid disease. Presumably, this is achieved by activating antioxidant defense, increasing oxygen delivery to the periphery, which helps reduce tissue hypoxia and improves glucose utilization, overcoming insulin resistance. The disadvantage of this method is that thyroid hormones are contrainsular, problematic to use in the absence of thyroid pathology, and this positive effect can cause due to weight loss and correction of atherogenic dyslipidemia. In this regard, the use of lipid-lowering drugs is pathogenetically more reasonable.

There is also a method for predicting diabetic peripheral neuropathy in children and adolescents (RF patent No. 2273028, publ. 03/27/2006). The method includes determining in peripheral blood a serological method of cerebral neurotrophic factor. When the magnitude of the studied neurotrophin is more than 9000 pg / ml, the subclinical stage of DPN is diagnosed. The method allows to predict the complication of type 1 diabetes in children and adolescents and to start preventive treatment in a timely manner. However, when implementing the method, the characteristics of the underlying disease, the degree of metabolic changes in the patient are not taken into account, which reduces the objectivity of the forecasting method, given the multifactorial nature of the formation of DPN.

The objective of the invention is to provide a method for predicting the effectiveness of the treatment of diabetic polyneuropathy using various combination schemes of hypoglycemic and hypodipidemic drugs, taking into account the initial parameters of carbohydrate and lipid metabolism, the severity of neuropathy and anamnestic data.

где е - основание натурального логарифма, е=2,72; Z - коэффициент регрессии, вычисляемый по формуле Z=4,56-0,05·ДлСД-0,02·ВырДПН-0,05·ТГ-0,53·HbAlc+0,14·СтрЛ, при этом если значение Р равно 0,7 или более, то у пациентов прогнозируют успешную коррекцию ДПН, а если значение Р имеет величину менее 0,7, то необходимо поменять стратегию лечения.This task is achieved by the fact that in patients the duration of type 2 diabetes (DLS) is determined in years, the severity of manifestations of diabetic polyneuropathy (VADD) is assessed by the scores of the neuropathic dysfunctional count questionnaire, the content of triglycerides (TG) and glycosylated hemoglobin (HbAlc) in the blood is determined before treatment . Choose a treatment strategy (StL), ranking as follows: 1 point - standard hypoglycemic therapy: metformin + diabeton MB; 2 points - sugar-lowering therapy with a combination of drugs that reduce insulin resistance and incretinomimetics (metformin + exenatide); 3 points - hypoglycemic and lipid-lowering therapy (metformin, exenatide, statins); 4 points - hypoglycemic and lipid-lowering therapy, including fibrates (metformin, exenatide, statins, fibrates). The probability of successful correction of DPN is determined by the formula $$P=\mathrm{one}-\frac{\mathrm{one}}{\mathrm{one}+e^{-(0,99-\mathrm{one},78\cdot Z)}},$$

where e is the base of the natural logarithm, e = 2.72; Z is the regression coefficient calculated by the formula Z = 4.56-0.05 · DlSD-0.02 · VyrDPN-0.05 · TG-0.53 · HbAlc + 0.14 · StR, while if the P value is 0.7 or more, then patients will predict a successful correction of DPN, and if the P value is less than 0.7, then it is necessary to change the treatment strategy.

The novelty of the invention lies in the fact that the simultaneous assessment of anamnestic data, carbohydrate and lipid metabolism parameters, points on the VAT scale, the use of multiple regression analysis, which is the main one in multivariate statistics, can increase the sensitivity of prognostic determination of treatment effectiveness even at the stage of planning for its use.

The invention has an inventive step, as for a specialist endocrinologist does not explicitly follow from the level of medicine in this field of diabetology.

In the available sources of information in Russia and foreign countries, a method similar to the proposed method for predicting the effectiveness of treatment of DPN was not found.

The claimed invention is industrially applicable, as it can be repeatedly repeated and used in assessing the effectiveness of treatment of DPN and reproduced in various medical and preventive and scientific medical institutions, especially endocrinological and therapeutic profile.

A method for predicting the effectiveness of treatment of diabetic polyneuropathy in patients with type 2 diabetes mellitus and dyslipidemia is as follows.

A patient with type 2 diabetes is specified when he was first diagnosed and the disease duration in years is determined - DLS.

The severity of peripheral polyneuropathy is determined on a scale of neuropathic dysfunctional counts (VAT) - Vyrrrrrrrh (Young MJ, Zhou YQ, Rodrigues E. et al. Variable relationship between peripheral somatic and autonomic neuropathy in patients with different syndromes of diabetic polyneuropathy // Diabetes. - 1986. - Vol.35. - P.192-197; Chernysheva T.E., Guryeva I.V., Altunbaev R.A. et al. Diabetic neuropathy (pathogenesis, diagnosis, treatment) .- M.: MEDICAL PRACTICE - M, 2006. - S.39-40) and rank points on the VAT scale in the following way: 1 point - initial DPN (number of points on the VAT questionnaire initial DPN (number of points for nick VAT 0-4 points) 2 points - moderate cash flow (the number of points on the questionnaire VAT 5-13 points) 3 points - severe cash flow (the number of points on a scale of VAT 14 points or more).

In the patient’s whole blood, the level of glycosylated hemoglobin is determined in%, for example, using the fast ion-exchange method using reagents from HUMAN, Germany (Ostapenko V.A., Firstova L.P., Eliseeva I.P. et al. Optimization of determination the stable fraction of glycosylated hemoglobin HbAlc by indexing the total fraction of glycosylated hemoglobin HbAl // Basic research. - 2008. - No. 6 - P.116-117).

In blood serum, the level of triglycerides in mmol / l is determined, for example, using the KliniTest-Cholesterol reagent kit manufactured by the Eco-Service Scientific and Production Center (A. Kishkun, Guidelines for laboratory diagnostic methods. - M .: GEOTAR - Media, 2007 .-- P.204).

Analyzing disorders of carbohydrate and lipid metabolism, a treatment regimen is determined from the four presented below, ranking it with an appropriate score: 1 point — standard sugar-lowering therapy: metformin + diabeton MB; 2 points - sugar-lowering therapy with a combination of drugs that reduce insulin resistance and incretinomimetics (metformin + exenatide); 3 points - hypoglycemic and lipid-lowering therapy (metformin, exenatide, statins); 4 points - hypoglycemic and lipid-lowering therapy, including fibrates (metformin, exenatide, statins, fibrates).

Next, calculate the regression coefficient Z by the formula:

Z = 4.56-0.05 · DlSD-0.02 · VyrDPN-0.05 · TG-0.53 · HbAlc + 0.14 · StL,

where DlSD - the duration of type 2 diabetes, determined in years;

VyrDPN - severity of DPN: 1 point - initial DPN (the number of points on the VAT questionnaire 0-4 points), 2 points - moderate DPN (the number of points on the VAT questionnaire 5-13 points), 3 points - expressed DPN (the number of points on the VAT scale 14 points or more);

TG - the content of blood triglycerides before treatment in mmol / l;

HbAlc - glycosylated hemoglobin before treatment in%;

StrL - the proposed treatment strategy: 1 point - standard hypoglycemic therapy: metformin + diabeton MB; 2 points - sugar-lowering therapy with a combination of drugs that reduce insulin resistance and incretinomimetics (metformin + exenatide); 3 points - hypoglycemic and lipid-lowering therapy (metformin, exenatide, statins); 4 points - hypoglycemic and lipid-lowering therapy, including fibrates (metformin, exenatide, statins, fibrates).

The calculated value of Z is substituted into the formula for determining the probability of successful correction of DPN in patients with type 2 diabetes and dyslipidemia (in fractions of one), which has the following form:

$$P=\mathrm{one}-\frac{\mathrm{one}}{\mathrm{one}+e^{-(0,99-\mathrm{one},78\cdot Z)}}$$

where e is the base of the natural logarithm, e = 2.72;

Z is the regression coefficient.

If the P value is 0.7 or more, then patients will be predicted successful correction of DPN. If the P value has a value less than 0.7, then it is necessary to change the treatment strategy and re-calculate P with a different number of points to choose a more successful method of combining drugs in an individual situation.

The proposed method excludes the presence of subjectivity. The method will allow the doctor to assess the possibility of successful correction of DPN, to predict its course, to prescribe adequate therapy in a timely manner. This will help reduce the risk of developing late vascular complications of diabetes and improve the health status and quality of life of patients.

The efficiency of the invention is confirmed by the following examples.

For example, in patient D., 58 years old, type 2 diabetes was diagnosed from 55 years old, lasted 3 years, according to the VAT questionnaire, the number of points was 11, therefore, the severity of DPN was moderate (2 points), before treatment, the content of blood triglycerides was 2, 1 mmol / L, glycosylated hemoglobin was 7.1%. The patient was prescribed a combination of hypoglycemic and hypolipidemic therapy - metformin, exenatide, simvastatin, treicor (4 points).

First, we calculate the coefficient Z = 4.56-0.05 · 3-0.02 · 2-0.05 · 2.1-0.53 · 7.1 + 0.14 · 4 = 1.04,

Then we substitute it into the formula

$$P=\mathrm{one}-\frac{\mathrm{one}}{\mathrm{one}+e^{-(0,99-\mathrm{one},78\cdot \mathrm{one},0\mathrm{four})}}$$

P = 0.7.

Therefore, the probability of successful correction of DPN in this clinical case is 0.7 or 70%.

Another clinical example. Patient A., 64 years old, had diabetes for 12 years, according to the VAT questionnaire, the number of points corresponded to 15, therefore, DPN was pronounced (3 points), the initial content of blood triglycerides was 2.6 mmol / L, glycosylated hemoglobin was 7.4% . The patient was prescribed only a hypoglycemic therapy - metformin and exenatide (2 points).

First, we calculate the coefficient Z = 4.56-0.05 · 12-0.02 · 3-0.05 · 2.6-0.53 · 7.4 + 0.14 · 2 = 0.06

Then we substitute it into the formula

$$P=\mathrm{one}-\frac{\mathrm{one}}{\mathrm{one}+e^{-(0,99-\mathrm{one},78\cdot 0,06)}}$$

P = 0.29.

Therefore, the probability of successful correction of DPN in this patient was low - 0.29 or 29% and determined the inappropriateness of using this method of treatment.

The determination significance of the totality of all studied parameters for predicting the likelihood of effective treatment of DPN was high, since the determination coefficient was R ² = 0.82. Therefore, the created regression model in 82% explained the effectiveness of the treatment. The Fisher test F was 27.3 (p <0.001), indicating a high statistical significance of the regression model. The multiple correlation coefficient, which reflects the relationship between the baseline and the likelihood of good treatment results, was 0.91, which testified to their strong influence. The coefficient of determination of residuals (i.e., unaccounted values in the model) was insignificant R ² = 0.12, which indicated that the risk of an uncontrolled flow was mainly explained by indicators taken into account in the regression model and depended little on unaccounted factors.

To verify the quality of the studied model, an ROC analysis was carried out with the construction of sensitivity and specificity curves. The ROC curve reflected the dependence of the number of correctly classified positive examples on the number of incorrectly classified negative examples. The calculated area under the ROC curve was 0.71, which corresponds to the "good" quality of the model.

The technical and economic effectiveness of the proposed method lies in the fact that the developed method allows you to choose an effective way to treat DPN and prevent the development of foot ulcers, diabetic foot syndrome, which helps to reduce the risk of patient disability and their loss of their social and labor potential.

Claims (1)

A method for predicting the effectiveness of treatment of diabetic polyneuropathy (DPN) in patients with type 2 diabetes mellitus (DM) and dyslipidemia, namely, in patients with type 2 diabetes and dyslipidemia, the duration of type 2 diabetes (DLS) in years is determined, the severity of manifestations of diabetic polyneuropathy is assessed (VyrDPN) taking into account the points of a neuropathic dysfunctional account (VAT): 1 point of severity of DPN corresponds to 0-4 points of a VAT questionnaire, 2 points of severity of DPN - 5-13 points of a VAT questionnaire, 3 points of severity of DPN - 14 and more points on the VAT questionnaire; determine the content of triglycerides (TG) and glycosylated hemoglobin (HbAlc) in the blood before treatment and choose a treatment strategy (StR): 1 point - standard sugar-lowering therapy - metformin + diabeton MB; 2 points - sugar-lowering therapy with a combination of drugs that reduce insulin resistance and incretinomimetics - metformin + exenatide; 3 points - hypoglycemic and lipid-lowering therapy - metformin + exenatide + statins; 4 points - sugar reducing and lipid-lowering therapy, including fibrates - metformin + exenatide + statins + fibrates; then determine the probability of successful correction of DPN in fractions of a unit according to the formula
$$P=\mathrm{one}-\frac{\mathrm{one}}{\mathrm{one}+e^{-(0,99-\mathrm{one},78\cdot Z)}},$$

where e is the base of the natural logarithm of e = 2.72; Z is the regression coefficient calculated by the formula Z = 4.56-0.05 · DlSD-0.02 · VyrDPN-0.05 · TG-0.53 · HbAlc + 0.14 StrL, while if the P value is 0, 7 or more, then patients will be predicted for successful correction of DPN, and if the P value is less than 0.7, then it is necessary to change the treatment strategy.