Thioctacid BV: analysis of recent studies
In clinical and experimental diabetology, significant advances have been made over the past 20 years, but despite this, the prevalence of diabetes mellitus continues to increase. According to WHO experts, by 2010 there will be more than 260 million people worldwide, and by 2025 - 360 million people with diabetes mellitus, of which about 90% will be patients with type 2 diabetes.
Table 1. TSS values at baseline and after 5 weeks
Graph 1. Weekly distribution of TSS in different study groups
The lifespan of patients with type 2 diabetes is reduced by 5-10 years. The diagnosis of these patients is usually made at 5-7 years of illness. At this time, 20-30% of patients already have complications such as retinopathy, nephropathy, neuropathy and angiopathy of various localizations (15).
Diabetic neuropathy (DNP) is one of the most common and difficult to treat late complications of diabetes, it is believed to develop in 30% of patients with diabetes. Unlike other chronic complications of diabetes (diabetic retinopathy and nephropathy), diabetic neuropathy can be accompanied by active clinical symptoms, often expressed, for example, by the development of pain, which significantly worsens the quality of life of patients. It should be especially emphasized that DNP is still poorly diagnosed; only 35% of doctors correctly diagnose DNP; therefore, about 50% of patients with a chronic painful form of neuropathy have never received pain treatment (16).
A number of studies (DCCT, UKPDS) have shown that the main factor in the prevention of diabetic neuropathy is normoglycemia, however, strict control of blood sugar levels may be accompanied by a significant increase in the frequency of severe hypoglycemia. It is well known that diabetic neuropathy is characterized by the presence of signs of neurological deficits, which in turn can be triggers for the development of ulcerative lesions of the foot with subsequent amputation. Thus, the current treatment option should be to eliminate the symptoms of painful neuropathy along with a decrease in neurological deficits (4). Currently, antidepressants, anticonvulsants and other drugs are used to treat the painful form of neuropathy, but all of them are aimed at relieving the symptoms of pain without affecting the pathogenetic mechanisms of neuropathy. Pathogenetic therapy is based on influencing the main pathogenetic components of DPN. In particular, aldose reductase inhibitors slow down the polyol pathway of glucose metabolism, thereby reducing the damaging effects of byproducts of this type of metabolism on the course of DPN (5, 6). Antioxidants, such as thioctic acid, act on free radicals and have an effect on oxidative stress. Nerve growth factors prevent deficits in neurotrophs and axonal transport (7). Aminoguanidine inhibits the glycation of proteins in nerve endings and the vascular wall (8). Currently, most studies assessing the effectiveness of one or another type of pathogenetic therapy for DPN have either been stopped due to the development of side effects or have not been completed (10, 11, 12). The exception is work on the effectiveness of thioctic (alpha-lipoic) acid preparations. Alpha lipoic acid (thioctic acid) is a natural coenzyme of the mitochondrial multienzyme complex that catalyzes the oxidation and decarboxylation of alpha-keto acids such as pyruvate and alpha-ketoglutorate. Thioctic acid is a powerful lipophilic antioxidant, which determines the possibility of therapeutic use. Thioctic acid introduced into the body is reduced mainly to dihydrolipoic acid, which provides the main therapeutic effects by acting as a trap for the main free radical superoxide, which forms late complications of diabetes mellitus. Dihydrolipoic acid itself is not used as a drug, because It oxidizes easily during storage (14).
Experimental studies on rats with streptozotocin and hereditary diabetes have shown that thioctic acid reduces lipid peroxidation, increases the activity of superoxide dismutase, improves endoneurial blood flow and the rate of propagation of excitation in the sciatic nerve, increases glucose utilization in cardiomyocytes, inhibits the development of cataracts, and prevents damage to the glomerular apparatus of the kidneys ( 19, 20).
Alpha lipoic acid is used to treat metal and fungal poisoning, non-alcoholic steatohepatitis, and alcoholic polyneuropathy, but the drug is most widely and successfully used in the treatment of diabetic polyneuropathy (19, 20).
In clinical studies using alpha-lipoic acid in patients with diabetes, improvements in microcirculation, endothelium-dependent reactions of the vascular wall, renal filtration function and glucose utilization, a decrease in lipid peroxidation and normalization of the content of oxide and stress proteins were noted (21, 22).
Clinical use of Thioctacid for the treatment of diabetic neuropathy began in the 1950s. and until 1980, doses of 30 to 300 mg (both intravenously and orally) were used. From 1988 to 1995, doses of Thioctacid were increased to 400-600 mg. The results obtained are contradictory, and for comparison, groups of patients receiving B vitamins were used. It seemed that only intravenous administration of Thioctacid was effective. In addition, the timing of treatment was not determined. Several placebo-controlled, randomized, double-blind studies have been conducted to address these issues. For the first time, thioctic acid preparations became widely known after the ALADIN 1
(
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alpha-
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ipoic
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i
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iabetic
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europathy).
In 328 outpatients with type 2 diabetes, the effectiveness and safety of intravenous Thioctacid (TIO) was assessed. Patients were divided into 4 groups: those receiving TIO at a dose of 100, 600, 1200 mg and placebo (14 infusions over 3 weeks). The main criterion for assessing neuropathy was the TSS (Total Symptom Score), which made it possible to assess the intensity of the main positive neurological symptoms, such as shooting pain, burning, numbness and parasthesia. The study demonstrated that at a dosage of 600 mg/day as an intravenous infusion, thioctic acid leads to a significant reduction in various symptoms of DPN, including pain, paresthesia, numbness, etc., compared with placebo, and also proposed adequate criteria for the evaluation of diabetic neuropathy , which were then used in further work, including the TSS scale in particular. Side effects (headache, nausea, vomiting) were more common at a dose of 1200 mg (13). ALADIN II
study assessed the effectiveness and safety of long-term oral thioctic acid for two years.
Three groups of patients received Thioctacid tablets: one group (18 people) received Thioctacid at a dose of 600 mg 2 times a day, the second (27 people) received a dose of 600 mg once a day, and the third group (20 people) received placebo. This study did not provide a clear answer to the question of the effectiveness of long-term use of the drug, but the safety of taking thioctic acid in doses of 600 and 1200 mg was proven. The soon to be published data from the NATHAN I
, which examined the dynamics of NIS and seven electrophysiological tests in patients with diabetic neuropathy when treated with Thioctacid tablets for 4 years in order to prevent or slow down diabetic polyneuropathy.
ALADIN III
study, in two outpatient groups of patients with type 2 diabetes (167 and 174 patients, respectively), the first stage was intravenous thioctic acid 600 mg for three weeks compared with placebo, followed by oral administration of 1800 mg for 6 months.
This study demonstrated a significant reduction in the severity of neuropathic symptoms with intravenous administration of thioctic acid and a tendency to improvement with its oral administration. However, the data obtained with oral administration of thioctic acid did not differ significantly from the placebo group. The reason could be the marked variability between centers in the assessment of neuropathy symptoms and the large number of study centers (n = 70). Overall, it is concluded that with long-term oral use of thioctic acid, it is necessary to evaluate not the effect on the symptoms of DPN, but the ability of the drug to slow the progression of neuropathy. In the only study evaluating the effectiveness of thioctic acid on the course of autonomic cardiac neuropathy, DEKAN
(73 patients), it was demonstrated that its oral administration at 800 mg per day for four months leads to a significant reduction in the manifestations of this condition in patients with type 2 diabetes compared to placebo .
It is interesting to note that the SYDNEY 1
(2) demonstrated the effect of Thioctacid 600T on all 4 main symptoms of neuropathy, summarized in the TSS scale (pain, burning, parasthesia, numbness).
These results were very important because drugs such as gabapentin, carbazepine, and tricyclic antidepressants can reduce either pain or paresthesia, but do not have a significant effect on all 4 main symptoms of DPN. Another important point in the study was the fact that there was a decrease in cardiac symptoms, and an improvement in signs of neurological deficits, assessed by the NIS scale, was also recorded. The NIS scale, proposed by Professor P. Dick for clinical studies, allows you to obtain more detailed information about the type of neurological disorder. This study involved 120 patients with type 1 and type 2 diabetes with symptoms of neuropathy, who were divided into 2 groups: patients in the first group received intravenous Thioctacid, the second group received placebo (0.04 mg riboflavin) for 3 weeks. Thus, treatment with Thioctacid 600T intravenously for three weeks has been shown to be effective and safe. The safety of the drug was confirmed by the absence of side effects compared to placebo. Then the question arose about the duration of the effect of intravenous administration of Thioctacid 600T; it turned out that the effect on neurological symptoms persisted for 6 months, and on neurological deficits for a month. In addition, it is known that 25% of patients do not respond to the oral drug, and the use of Thioctacid 600T intravenously is more traumatic than oral administration, and this type of use is not always possible for working diabetics, patients in the older age group and patients with severe symptoms of chronic renal failure. In this regard, Viatris has developed a new technology that has improved bioavailability parameters in the tablet form. This form was named Thioctacid BV, a modified dosage form of thioctic acid with improved pharmacokinetics, which has a number of advantages over the conventional form. The tablet form of Thioctacid BV has interindividual variability - only 22%, compared with the previous form - 59% (18). The company again faced the question of the possible effective dosage of Thioctacid BV, and the possibility of replacing intravenous administration with a tablet course. And finally, just recently, the SYDNEY II study was conducted, which answered all these questions. SYDNEY II
study is a multicenter, randomized, double-blind, placebo-controlled study conducted in 5 centers (three centers in Russia and two centers in Israel). A total of 181 patients took part in the study (1). Initially, the effectiveness was studied using the main TSS and NIS scales of three different doses of Thioctacid BV-600, 1200 and 1800 mg for 5 weeks of the main dose and one week of placebo administration, to identify placebo-dependent patients. 45 patients received Thioctacid BV at a dose of 600 mg, 47 patients received 1200 mg, 46 patients received 1800 mg, and 43 patients received placebo throughout the study. As a result, 227 patients were screened, 40 of them had glycated hemoglobin above 10%, 187 patients entered the placebo phase for one week, in the end, 181 patients were randomized, 166 patients completed the study, 12 had side effects, 1 patient in the placebo group, 5 in the 1200 mg group and 6 in the 1800 mg group.
TSS values at baseline and after 5 weeks of the study are presented in Table 1.
As can be seen from Table 1, statistically significant differences in the groups are observed compared to placebo, the overall score was reduced due to a decrease in pain and burning, but there were no differences between groups. This is also confirmed by the data in Chart 1.
Graph 1 shows that there was a significant decrease in TSS in all groups compared to placebo, starting from the second week, only in the group taking Thioctacid at a dose of 1800 mg, a decrease in TSS was noted already from the first week of administration. In addition, it should be noted that during the study, a significant decrease in the values of scales responsible for neurological deficits was noted. Improvement in neurological status was noted in all three groups receiving Thioctacid. However, as noted above, in 11 patients receiving Thioctacid, side effects were noted, the most common of which were nausea and vomiting; these side effects turned out to be dose-dependent (21% in patients at a dose of 1200 mg and 48% at a dose of 1800 mg). mg). In this regard, I would like to mention a study conducted at the Moscow Endocrinological Dispensary
. The study was open randomized with comparison groups. The first group consisted of 15 patients with DPN who received Thioctacid BV orally 600 mg three times a day for four weeks; the second – 15 patients with DPN who received Thioctacid BV orally at 600 mg per day for three months. Taking the immediate-release thioctic acid drug (Thioctacid BV) at 1800 mg per day for four weeks or 600 mg per day for three months led to a significant reduction in the severity of neuropathic complaints in patients with diabetes. And taking Thioctacid BV 600 mg three times a day did not lead to side effects (17).
This study demonstrated the positive effect of a single dose of Thioctacid BV at a dose of 600-1800 mg for 5 weeks. Using a dose of 600 mg per day leads to a decrease in neurological symptoms after 3 weeks of use (3); when using higher doses of the drug, the effect can be achieved after 1-2 weeks of use. Neurological deficits are reduced with doses of 600 mg, 1200 mg and 1800 mg.
The question remains about the possibility of using Thioctacid for other complications of diabetes mellitus. There are no placebo-controlled studies on the effect of Thioctacid on diabetic retinopathy and nephropathy. However, pilot studies continue to be conducted. Such a study on the effect of Thioctacid on diabetic retinopathy
was carried out at the MNTK "Eye Microsurgery" named after. Academician S.N. Fedorov. We examined 17 patients with diabetes mellitus types 2 and 1 (15/2), aged from 22 to 71 years with a diabetes duration of up to 15 years, with an HbAlC level of 7.5±1.4. All patients were examined not only for the condition of the fundus, but also for peripheral neuropathy using the TSS Scale and the Thio-Term test. All patients had painful peripheral neuropathy with TSS 8.66±1.2 points and proliferative diabetic retinopathy. The examined patients received 1800 mg of Thioctacid BV for 3 weeks. As a result, all patients with diabetic proliferative retinopathy did not have worsening of diabetic retinopathy, while a minimal relative risk (1.01) was identified for the progression of proliferative diabetic retinopathy during the use of Thioctacid BV at a dosage of 1800 mg per day. The condition of neuropathy improved significantly, the TSS scale decreased to 5.4b±1.4 (p
The following conclusions were made in the study.
1. Thioctacid BV 1800 mg per day for 3 weeks is effective for the treatment of diabetic peripheral neuropathy.
2. There is no risk of progression of proliferative diabetic retinopathy when using Thioctacid BV at a dose of 600-1800 mg.
In 2008, T.A. Soluyanova’s dissertation was defended, based on research data using Thioctacid BV. It was once again shown that pain reduction occurred from the second week of taking Thioctacid at a daily dose of 1800 mg, from the fourth week of taking it at a dose of 1200 mg, and only by the fifth week of taking it at a dose of 600 mg. A significant decrease in neurological symptoms over time was detected in the group taking Thioctacid 600 mg; in the group using Thioctacid 1800 mg, there was a tendency towards positive dynamics in neurological symptoms (according to myography). In the presence of pain as the predominant symptom of diabetic neuropathy, it is advisable to begin treatment with 1800 mg of Thioctacid BV, taking into account the dose-dependent effect of the development of side effects; in all other cases, the optimal dose remains 600 mg per day (23).
Obviously, the choice of treatment regimen for DPN using Thioctacid BV should be individual and depend on the specific situation. For example, in case of severe pain symptoms that debilitate the patient, and there is no possibility of intravenous treatment, a shorter course with a fairly high dosage of the drug (1800 mg/day for four weeks) can be prescribed. On the contrary, for symptoms that are not so pronounced, preference may be given to a longer course with a lower daily dosage (600 mg/day). In addition, Thioctacid BV can be successfully used for other complications of diabetes without the threat of their further progression.
A.S. Ametov
RMAPO, Moscow Distal symmetric sensory or sensorimotor polyneuropathy (DPN) is the most important clinical manifestation of diabetic neuropathy and develops in approximately 30% of patients with diabetes. The most important etiological factors associated with the development of DPN are poor glycemic control and duration of diabetes. At the same time, arterial hypertension, age, smoking, hypoinsulinemia and dyslipidemia play a potential role in the development of DPN. Data are emerging in the domestic and foreign literature suggesting that not only markers of microangiopathy such as albuminuria, but also those used to diagnose polyneuropathy, such as nerve conduction velocity (NCV) and vibration sensitivity threshold (VST), can predict mortality rate in patients with diabetes. An increased vibration sensitivity threshold also predicts the development of neuropathic foot ulcers, one of the most common causes of hospitalization and limb amputation in patients with diabetes. It should be especially emphasized that DPN is still underdiagnosed. Thus, only 35.6% of endocrinologists and 30.7% of doctors of other specialties correctly identify mild and moderate forms of DPN. Another surprising finding was that only 50% of patients with chronic painful neuropathy never received pain treatment (Daousi et al., 2004). In addition, a study carried out by Professor D. Ziegler (2005) showed that the prevalence of diabetic neuropathy in patients with diabetes, in people with impaired glucose tolerance and in people without diabetes was 27, 13 and 8%, respectively. These data suggest that distal symmetric neuropathy develops very early. It is well known that the clinical picture of diabetic neuropathy is characterized by the presence of symptoms of painful neuropathy, which significantly reduce the quality of life of patients with diabetes. Moreover, diabetic neuropathy is characterized by the presence of signs of neuropathic deficiency, which in turn can be triggers for the development of ulcerative lesions of the foot with subsequent amputation. Thus, the current treatment option for DPN should be to eliminate the symptoms of painful neuropathy along with reducing the neuropathic deficit. It is important to emphasize that in order to determine the clinically significant effect of the drug on diabetic polyneuropathy, combined scales for assessing neuropathic symptoms and deficits have recently been proposed. Symptoms can be scored using the TSS, which summarizes the intensity and frequency of major neuropathic symptoms such as pain, paresthesia, burning and numbness. While the NIS scale, proposed by Professor P. Dick specifically for clinical studies, provides more detailed information - electromyographic indicators, threshold of vibration and temperature sensitivity, heart rate variability during deep breathing. New possible types of therapeutic treatment are currently being studied, based on the results of modern research regarding the pathogenetic mechanisms of the development of DPN. Until now, with the exception of thioctic acid, none of the drugs have been available for use in clinical practice. However, patients with DPN often require additional pharmacological treatment to relieve pain and maintain quality of life. Although pain treatment with antidepressants is effective, the value of such therapy is limited by the frequency of side effects. Other symptomatic approaches, including the use of anticonvulsants, tramadol, and others, were not sufficiently effective or had incomplete effect. Moreover, these drugs were designed to relieve symptoms without affecting the underlying neuropathy. When studying the effectiveness of thioctic acid, several placebo-controlled, randomized, double-blind studies with the same design were analyzed. Analyzing the results of studies such as Aladin-I, Aladin-II, Sydney-I and Nathan-II, where all patients received 600 mg of thioctic acid (Thioctacid 600T) intravenously for three weeks, the clinical effectiveness of this drug was shown for neuropathic symptoms , and for neuropathic deficits. It is important to note that the meta-analysis conducted by D. Ziegler (2005) showed similar results to these studies. It is interesting to note that the Sydney study demonstrated the effect of Thioctacid 600T on all four major symptoms of DPN, summarized in the Total Symptom Score (TSS). In particular, a statistically significant decrease in TSS indicators was recorded in the Thioctacid 600T group compared to the placebo group. Thioctacid 600T had a significant effect on neuropathic pain, burning, paresthesia and numbness. These results have very important scientific and practical implications due to the fact that other types of treatment, such as gabapentin, carbazepine or tricyclic antidepressants, can reduce either pain or paresthesia, but do not have such a pronounced therapeutic effect on all four main symptoms. A fundamentally important point in the Sydney study was the fact that, along with a decrease in cardiac symptoms, there was a concomitant improvement in signs of neuropathic deficits, summarized in the NIS scale, in the Thioctacid 600T group compared with the placebo group. Thus, treatment with thioctic acid (Thioctacid 600T) at a dose of 600 mg intravenously for three weeks has been shown to be effective and safe. The safety of this drug was confirmed by the absence of an increase in side effects compared to the placebo group. Of undoubted practical interest were the data regarding the duration of the clinical effect in the Thioctacid 600T group. It was clearly shown that the effects of the drug on TSS and NIS values only lasted for one month. At the same time, 6 months after the end of the course of treatment, it was noted that the effect of thioctic acid on neuropathic symptoms persisted, although it was not as effective compared to the initial result, but still pronounced compared to the placebo group. However, the effect of intravenous administration of thioctic acid on indicators of neuropathic deficits persisted only for a month after the end of a three-week course of intravenous administration. However, while recording the good effectiveness of thioctic acid, it should be especially noted that about 20-30% of patients do not respond to the oral drug. Analyzing the possible causes of impaired absorption of thioctic acid, experts came to the conclusion that this may be due to the critical bioavailability of the drug. In this regard, Viatris has developed a special technology that was aimed specifically at improving the bioavailability parameters of the tablet form of the drug. Such a drug today is Thioctacid BV (rapid release), which allows one to overcome the increased variability of absorption characteristic of conventional tablet forms of thioctic acid. Thioctacid BV has predictable pharmacokinetics, providing the necessary therapeutic concentration of the active substance in tissues, and has higher bioavailability than previous generation thioctic acid tablets. The main disadvantage of conventional forms of thioctic acid was the high variability in the time to reach maximum plasma concentration (59%), even in the same patient, as a result of which in some patients the level of the drug in plasma and tissues may be below therapeutic levels. The tablet form of Thioctacid BV, due to faster and more pronounced absorption, has interindividual variability of only 22%. Taking Thioctacid BV tablets 20-30 minutes after meals provides a reliable increase in the concentration of thioctic acid in the blood in all patients, which cannot be guaranteed when taking conventional oral forms of the drug. It should be noted that almost all patients responded quickly and equally to Thioctacid BV, which is important in real practical life. Finally, the Sydney-II study was completed relatively recently, which was primarily devoted to determining the dose of oral Thioctacid BV, which could effectively replace 600 mg of the drug administered intravenously. Moreover, when assessing the effectiveness of the oral form of Thioctacid BV, its effect on both cardiac symptoms of DPN and signs of neuropathic deficiency was studied, which would confirm the pathogenetic validity of the concept of using alpha-lipoic acid in principle. The Sydney-II study was carried out in five centers (three centers in Moscow, two centers in Israel). Initially, the effectiveness of three different doses of Thioctacid BV was studied - 600, 1200 and 1800 mg by determining the total symptom score (TSS) and the NIS scale, which allows studying neuropathic deficits. It should be noted that all three dosages of Thioctacid BV reduced TSS by an average of 4.7 points. Moreover, these results were statistically significantly different from the placebo group. To the surprise of all researchers, the most effective oral dose of Thioctacid BV was a dose of 600 mg, where the best results were obtained in reducing cardiac symptoms of DPN. Similar results were obtained for neuropathic deficits. In addition, a correlation was noted with respect to the dose of Thioctacid BV and side effects, since there were no statistically significant differences between the dose of Thioctacid BV 600 mg and the placebo group. Thus, Thioctacid BV at a dose of 600 mg when administered orally showed the same effect as Thioctacid 600T administered intravenously, which was convincingly demonstrated in the Sydney-II study and will undoubtedly find its place in the practice of a clinician, since intravenous administration drugs are always more traumatic for patients than taking tablet forms.
Literature 1. Ametov A.S., Strokov I.A. Diabetic polyneuropathy: present and future // Russian Medical Bulletin. 2001. T. 6. No. 1. P. 35-40. 2. Strokov I.A., Barinov A.N., Novosadova M.V. Treatment of diabetic polyneuropathy // Breast cancer. 2001. T. 9. No. 7. P. 3145-317. 3. Ametov A.S., Strokov I.A., Samigullin R.R. Antioxidant therapy of diabetic polyneuropathy // Breast Cancer. 2005. T. 13. No. 6. P. 339-343. 4. Ziegler D. Thioctic acid: A critical review of its effects in patients with symptomatic diabetic polyneuropathy // Treat Endocrinol. 2004. Vol. 3. P. 173-189.
