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Международный эндокринологический журнал Том 18, №8, 2022

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Сучасні можливості впливу на основні фактори серцево-судинного ризику у хворих на цукровий діабет 2-го типу

Сучасні можливості впливу на основні фактори серцево-судинного ризику у хворих на цукровий діабет 2-го типу

Авторы: O.Ya. Kobrynska, O.M. Didushko
Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine

Рубрики: Эндокринология

Разделы: Клинические исследования

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Резюме

Актуальність. У пацієнтів iз цукровим діабетом (ЦД) відзначається вірогіднe зростання серцево-судинної захворюваності. Встановлено кореляцію між резистентністю до лептину та серцево-судинним ризиком у пацієнтів з артеріальною гіпертензією та метаболічним синдромом. Проте немає даних про вплив емпагліфлозину на рівень лептину, а також про ефективність емпагліфлозину щодо ключових серцево-судинних факторів ризику у хворих на ЦД з нормальною та надлишковою масою тіла. Мета: вивчити вплив комплексного лікування із застосуванням метформіну та емпагліфлозину на основні фактори серцево-судинного ризику у хворих на цукровий діабет 2-го типу з різною масою тіла. Матеріали та методи. Проведено обстеження 97 пацієнтів із ЦД 2-го типу з нормальною, надлишковою масою тіла та ожирінням. Знято антропометричні показники. Визначено показники вуглеводного, ліпідного обмінів, рівень лептину в сироватці крові та розраховано індекс HOMA. Результати. Інсулінорезистентність у всіх групах хворих асоціювалась із абдомінальним типом ожиріння, гіперлептинемією (r = 0,505, р < 0,05; r = 0,846, р < 0,05; r = 0,886, р < 0,05 у пацієнтів І–ІІІ груп). Після проведеного 6-місячного курсу лікування метформіном та емпагліфлозином вірогідно знизилися маса тіла та окруж­ність талії у хворих із надмірною вагою та ожирінням, у пацієнтів із нормальним індексом маси тіла вірогідних змін між групами не виявлено. Зазначено вірогідний позитивний вплив комплексного лікування на показники вуглеводного обміну, систолічний артеріальний тиск незалежно від ваги пацієнта. Під впливом комплексного лікування із застосуванням емпагліфлозину вірогідно знизилися рівень лептину (p < 0,05) та індекс HOMA (p < 0,05) у пацієнтів усіх груп незалежно від індексу маси тіла. Висновки. У результаті дослідження встановлено, що застосування емпагліфлозину та метформіну протягом шести місяців мало вірогідний вплив на модифіковані чинники серцево-судинного ризику у хворих на ЦД 2-го типу з різною масою тіла.

Background. Cardiovascular morbidity increases notably among patients with diabetes. A correlation between leptin resistance and cardiovascular risk was found in patients with arterial hypertension and metabolic syndrome. However, there are no data about the influence of empagliflozin on leptin level; empagliflozin effectiveness against key cardiovascular risk factors in diabetic patients with normal weight and overweight has not been studied yet. The purpose of this work was to study the impact of comprehensive treatment using metformin and empagliflozin on the main cardiovascular risk factors in patients with type 2 diabetes mellitus with different body weights. Materials and methods. Ninety-seven patients with type 2 diabetes with normal weight, overweight and obesity were examined. Anthropometric indicators were taken. The parameters of carbohydrate and lipid metabolism, the level of leptin in blood serum were determined and the HOMA-IR was calculated. Results. Insulin resistance in all groups of patients was associated with abdominal obesity, hyperleptinemia (r = 0.505, p < 0.05; r = 0.846, p < 0.05; r = 0.886, p < 0.05 in patients of groups I–III). After a 6-month course of treatment with metformin and empagliflozin, body weight and waist circumference significantly decreased in overweight and obese patients, and no significant changes between groups were found in those with a normal body mass index. A reliable positive effect of comprehensive treatment on indicators of carbohydrate metabolism, systolic blood pressure, regardless of the patient’s weight, was noted. Under the influence of comprehensive treatment with the use of empagliflozin, the level of leptin (p < 0.05) and HOMA-IR (p < 0.05) also decreased significantly in patients of all groups, regardless of body mass index. Conclusions. It was found that the combined use of metformin and empagliflozin for 6 months had a reliable effect on the modified cardiovascular risk factors in patients with type 2 diabetes of different weights.


Ключевые слова

цукровий діабет 2-го типу; серцево-судинні фактори ризику; емпагліфлозин; надлишкова маса тіла; ожиріння

diabetes mellitus type 2; cardiovascular risk factors; empagliflozin; overweight; obesity

doi: http://dx.doi.org/10.22141/2224-0721.18.8.2022.1220

Introduction

Cardiovascular morbidity increases notably among patients with diabetes mellitus (DM). According to the WHO evaluations, 17 billion (30 % from all death cases) die from cardiovascular diseases (CVD) every year [1]. According to recent data, CVDs cause more than 4 billion deaths along with the whole of Europe every year that is 45 % of all deaths. Herewith the CVDs are 49 % of all deaths in females and 40 % of all deaths in males. According to recent data, mortality from the CVDs decreased in 12 European countries [2]. It is important to notice that in the last decades, there is sufficient evidence basis of that that increased CVD risk occurs in a (very) young age [3].
A correlation between leptin resistance and cardiovascular risk was found in patients with arterial hypertension and metabolic syndrome [4–6].
Apart from overweight, hyperleptinemia has been also associated with hypertension and insulin resistance [7, 8]. The peripheral actions of leptin include stimulation of inflammatory reaction, oxidative stress, atherogenesis, and thrombosis, thus promoting endothelial dysfunction, arterial stiffness, development and vulnerability of atherosclerotic plaques [10–12]. Furthermore, leptin regulates bone homeostasis, reproduction, and angiogenesis [13, 14]. There is a positive correlation between leptin levels in blood and insulin sensitivity, body mass index, waist circumference, hyperglycemia [15]. Elevated leptin concentrations have also been related to the incidence and progression of chronic kidney disease as well as insulin resistance, type 2 DM (T2DM), micro- and macrovascular diabetic complications. Statins and antidiabetic drugs (including sitagliptin, metformin, pioglitazone, liraglutide, and empagliflozin) may affect leptin levels [16].
According to the American Diabetes Association (ADA, 2020) and the European Society of Cardiology (ESC, 2019) guidelines, it is appropriate to use SGLT2 inhibitors and GLP-1 agonists as first- and second-line drugs for patients with atherosclerosis and high risk or presence of heart failure [17, 18]. It is necessary to mention that according to the EMPA-REG OUTCOME study, empagliflozin decreased significantly statistically cardiovascular (by 38 %) and general (by 32 %) mortality. Besides that, the number of hospitalizations due to heart failure decreased by 35 % [19]. During the whole study period, empagliflozin intake was associated with decreasing in body weight, waist circumference, uric acid level, systolic blood pressure (SBP) compared to placebo without increased heart rate, however with the mild, but statistically significant increase of HDL level [20]. G. Schernthaner et al. suggest that the addition of both empagliflozin and pioglitazone to metformin might be relatively the best option to reduce high cardiovascular morbidity and mortality of patients with T2DM and already present cardiovascular complications [21].
However, at the moment, there are no data about the influence of empagliflozin on leptin level, empagliflozin effectiveness against key cardiovascular risk factors in diabetic patients with normal weight and overweight has not been studied yet.
The purpose was to study the effectiveness of empagliflozin influence on key cardiovascular risk factors in diabetic patients with normal weight and, overweight and obesity.

Materials and methods

In the Department of Therapy 1 of Ivano-Frankivsk Central City Clinical Hospital, 97 patients with DM type 2 (WHO criteria 1999) were examined, who were getting metformin for not less than 6 months, but had not reached the HbA1c target (at the moment of inclusion into the study > 7.5 %, but < 9 %), as well as 10 practically healthy people.
The patients’ average age was 46.9 ± 3.2 years. The patients had no cardiovascular diseases and complications except AH in anamnesis and at the time of examination. The patients were not included in the study, if they had GFR < 60 ml/min/1.73 m2, rare genetic disorders (lactase deficiency, lactose intolerance, glucose-galactose malabsorption), as well as other contraindications for empagliflozin indicated in its instruction on application.
All patients got the general clinical examination that included the measure of height, weight, body mass index (BMI) or Quetelet’s index, waist circumference (WC), blood pressure (BP). Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) levels in blood serum were determined with the fermentation method. Low-density lipoprotein cholesterol (LDL-C) levels were calculated using the Friеdеwald formula. Carbohydrate metabolism was evaluated by blood glucose and glycated hemoglobin levels. We performed general cardiovascular risk stratification depending on systolic blood pressure (SBP), diastolic blood pressure (DBP), risk factors, asymptomatic target organ damage, DM, chronic kidney disease and cardiovascular diseases which had manifested clinically according to ESH (2019) [18]. Leptin levels (3.7–11.1 ng/ml in norm) were determined with the help of the Diagnostics Biochem Canada Inc kit. Obligator instrumental examination included blood pressure measuring. Anthropomorphic characteristics were determined with the evaluation of body mass index (BMI) calculated using the Quetelet’s formula (BMI = BW/H2, where BW is the body weight, kg; H is the height, m). To find out the obesity type, the waist-to-hip ratio was calculated. To control fasting carbohydrate metabolism, glucose concentration was evaluated by the glucose oxidase method. The endogenous insulin (ЕІ) level was determined by enzyme-linked immunosorbent assay with the DRG Diagnostics tests (Germany). Insulin resistance was assessed with the НОМА-ІR = (fasting glucose (mmol/L) × fasting insulin (μIU/ml))/22.5).
Statistical analysis was performed by analysis of variance. While analyzing materials, we calculated means (M), their standard errors (m), and confidence interval. Statistical significance was evaluated with Student’s t-test for dependent and independent samples; nonparametric Mann-Whitney U, Wilkonson W tests were used at the irregularity in the distribution. Differences were considered probable at р < 0.05. Association between variables was evaluated by Spearman’s rank correlation. Statistical data processing was performed with the help of variational and descriptive statistics using standard analytics packages Statistica 6.0, Foxbase, Excel 6.0 on the personal computer Pentium III. Local ethics committee approval was obtained for the study (number: 2020-08).

Results

The patients were randomized in 3 groups depending on BMI. Group І consisted of 29 patients with BMI < 24.9 kg/m2 (23.70 ± 0.13), group ІІ had 34 patients with BMI 24.9–29.9 kg/m2 (28.33 ± 0.20) and group ІІI — 34 patients with BMI > 30.0 kg/m2 (33.18 ± 0.40). Leptin, lipid panel, insulin resistance values for the patients of these groups are presented in Table 1.
During the examination of the patients, we found out that in group І high cardiovascular risk was in 70.6 % of females, very high one was in 29.4 %; in group ІІ high risk was in 64.7 % and very high one in 35.3 % of women; in group ІІІ high risk was in 58.3 % and very high one in 41.7 % of women. Among males (group І), 75 % had high cardiovascular risk and 25 % very high one, whilst in group ІІ 66.6 % had high, and 33.4 % very high risk, in group ІІІ — 60 % had high, and 40 % very high risk. In patients of all groups, there was a correlative association between leptin levels and cardiovascular risk factors.
Depending on administered treatment, all patients were randomized into 6 groups (Table 2). All included into the study patients were administered with the hypocaloric diet with limited intake of easily digested carbohydrates and saturated fats (1800 kcal/day, daily calorie intake was calculated by the formula recommended by WHO (1998) for each patient individually), besides that they were recommended to extend physical activity (walking 5 thousand steps per day). The patients of groups IA and IIA got metformin in individual doses as basic therapy. The patients of groups IB and IIB were administered empagliflozin 10 mg/day besides metformin. The patients continued taking administered earlier hypotensive, hypolipidemic therapy during the whole study without its correction.
After the 6-month treatment course with using SGLT2 inhibitors was done, the positive key cardiovascular risk factors dynamics was observed. So, the SBP and DBP values dynamics was more expressed in examined patients under the influence of the complex therapy with using of empagliflozin compared to the basic therapy as in males, as well as in females. Especially, SBP decreased by 11.82 % (р < 0.05) in group IB and by 12.4 % (р < 0.05) in group IIB and DBP decreased by 8.15 % (р < 0.05) and 8.3 % (р < 0.05) that was less expressed in groups of comparison. Under the influence of the therapy course, positive dynamics of carbohydrate metabolism which was probable in the patients of groups IB and IIB who were taking SGLT2 inhibitor additionally compared to the patients of groups ІА and ІІА (Table 3). For example, in the patients of group IB fasting glycemia decreased by 27.19 % (р < 0.05), HbA1с by 10.13 % (р < 0.05); in the patients of group IIB by 16.28 % (р < 0.05) and HbA1с by 11.1 % (р < 0.05) respectively (Table 3). In our opinion, probable decrease by 41.9 % (р < 0.05) of HOMA-IR in the patients of group IIB was important; in other groups, probable changes were not found (Table 3). In the process of treatment, BMI decrease was observed in not all groups. In the patients of groups ІА and IB, probable dynamics in decreasing weight was not observed (Table 3). So, in groups ІА and IB, BMI decrease was unreliable and did not depend on received therapy (р > 0.05). In group ІІА there was no probable BMI decrease (р > 0.05); unlike in group ІІА, in group IIB BMI decrease was probable from 27.82 ± 0.35 to 25.10 ± 0.50 (р < 0.05) (Table 3). But WC decreased reliably (р < 0.05) as in males, as well as in females of groups IB and IIB (Table 3). While analyzing received results, we noticed the probable influence of empagliflozin on the leptin le–vel. So, in patients with normal BMI, who got empagliflozin (group IB), it decreased by 39.5 % (р < 0.05), and the group of patients with overweight (IIB) by 29 % (р < 0.05), and the group of patients with obesity (IIІB) by 16 % (р < 0.05) while taking empagliflozin; in groups without empagliflozin reliable dynamics of leptin level was not observed (Table 3). The probable dynamics of lipid profile was not observed in any group (Table 3). Empagliflozin did not influence reliably hepatic values (AST, ALT). By evaluation of empagliflozin safety/tolerance, we also paid attention to serum creatinine/GFR values. Statistically significant changes in these values were not present in our patients. All participants finished the study; nobody from them presented side effects. Moreover, to evaluate empagliflozin safety, total urine analyses, in which there were found no statistically significant abnormalities in any participant, were done for the patients on each visit.

Discussion

The main conclusions of this study show that an SGLT2 selective inhibitor empagliflozin influences key cardiovascular risk factors. Under the influence of empagliflozin, systolic blood pressure improves; glycemia indices reliably decrease, independently of BMI. Importantly no patient had hypoglycemia that was confirmed by other authors too [19–21]. Several authors point out the pleiotropic effect of empagliflozin on the improvement of cardiac activity in animals with obesity without diabetes [24, 25]. Recently published new data show that in the post-myocardial infarction setting, empagliflozin had major beneficial effects on the principal load-independent measures of systolic function, preload recruitable stroke work and end-systolic pressure-volume relationship. In these non-diabetic animals, empagliflozin did not affect glycemia, as assessed by HbA1c, in both sham and post-MI groups [26]. Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction too [26].
An important cardiovascular risk factor is weight. But the problem of using of SGLT2 inhibitors in patients with normal BMI remains debatable. In or std, BMI and HOMA-IR decreased significantly under the influence of empagliflozin only in patients with overweight; the patients with normal BMI got their weight decreased, but not significantly, whereas other studies conducted on animals showed probable weight decrease by empagliflozin intake [25–27]. Possibly, these changes were interrelated with probable leptin level decrease, as well as the influence of empagliflozin on visceral fat. G.S. Papaetis found out also the significant influence of empagliflozin on HbA1c levels, chronic non-specific inflammation (including CRP) and immune resistance markers (leptin, HOMA-IR) in patients with DM type 2 and obesity [28]. Several experimental works point out the decrease of TG and TC levels [23, 27], other show increased HDL-C. In our study, we did not find out the reliable dynamics of lipid profile in any group.

Conclusions

Using of the SGLT2 inhibitor empagliflozin in the complex therapy of patients with diabetes mellitus type 2 and different bodyweight increase therapy effectiveness by positive dynamics of key cardiovascular risk factors, particularly decrease of body weight, waist circumference, blood pressure, carbohydrate metabolism indices and insulin resistance, leptin in particular.
 
Received 02.11.2022
Revised 05.12.2022
Accepted 14.12.2022

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