Diabetes CF in national and international recommendations
Due to the scale of its spread, type 2 diabetes has become an epidemic. This disease is characterized by serious complications if not managed effectively. Currently, seven classes of antidiabetic drugs are used to control glycemia in Russia, among which sulfonylurea derivatives occupy a special place. The article discusses sulfonylurea drugs, which differ not only in terms of the risk of hypoglycemia, but also in their cardiovascular and renal safety profiles. Particular attention is paid to one of the safest and most effective drugs in this group – Diabeton MV (modified release gliclazide). The features of its pharmacokinetics, dosage regimen, absorption rate, binding affinity to a specific receptor, and structural features that determine the antioxidant effect are presented. A comparison was made with drugs of the newest classes - inhibitors of dipeptidyl peptidase 4 and sodium-glucose cotransporter 2.
Rice. 1. Mechanism of insulin release in response to SCI
Rice. 2. Type of SUR receptors and different groups of drugs
Introduction
In 2006, United Nations experts adopted resolution 61/225, which recognized diabetes mellitus (DM) as a non-communicable epidemic affecting populations worldwide and a disease no less life-threatening than HIV/AIDS. For comparison, 1.5 million people died from AIDS in 2013, and 5 million from diabetes in 2015. Adverse outcomes in patients with diabetes are primarily due to its micro- and macrovascular complications, which formed the basis for the acrostic about diabetes “ SAGA":
- Leborrhea
occurs 25 times more often in patients with diabetes than in people without diabetes. - And
the amputation of limbs is 17–45 times, - Hemodialysis
– from 21.7 to 32.4% of all cases of end-stage chronic renal failure, - And
orthocoronary bypass surgery and stenting - from 15 to 25% of cases.
In 2021, there were 425 million people with diabetes in the world [1]. If we add up the number of people with diagnosed (425 million) and undiagnosed diabetes (200 million), as well as with prediabetes (300 million), then last year, out of the 7.5 billion population of the planet, approximately 1 billion had some kind of carbohydrate disorder. exchange. By 2045, the number of patients with diabetes may reach 629 million. According to forecasts, the prevalence of the disease in North America will increase by 35%, Southeast Asia by 84%, and in the Middle East and North Africa by 110%.
Achieving glycemic control, maintaining it for a long time, preventing the development of micro- and macrovascular complications, maintaining the quality of life of patients are recognized as the main objectives of the treatment of type 2 diabetes. The key to successfully solving them is a patient-centered approach. The latter means that the treatment strategy should be discussed with the patient, taking into account the characteristics of both the patient and the prescribed drug.
Recently, approval was received for the use of a number of new drugs for type 2 diabetes, which led to a revision of the basic treatment algorithms. For most patients, metformin remains the first-line drug. Sulfonylurea derivatives (SUMs) retain their positions as second- and third-line drugs. Such solutions are based on proven effectiveness and safety, extensive clinical experience, ease of use, the possibility of combination with other glucose-lowering drugs, and low cost.
The mechanism of action of sulfonylurea derivatives and its clinical significance
Sulfonylurea derivatives have been used in clinical practice since the late 1950s. Over this period, they demonstrated comparable effectiveness in reducing glycated hemoglobin (HbA1c) levels, but their characteristics with respect to the development of adverse reactions were unique. As a result, clinically significant intraclass differences.
Drugs in this group belong to the secretagogues, that is, they stimulate the secretion of insulin by beta cells of the pancreas. Modern PSMs realize their insulin-stimulating potential through adenosine triphosphate-dependent potassium channels (ATP-dependent K channels) (Fig. 1).
Sulfonylurea receptors (SURs) are an integral component of ATP-dependent K channels [2]. Each channel consists of four Kir6.2 proteins, which form a central pore in the cell membrane for the selective transport of potassium ions, and four SUR subunits, regulatory receptors. SUR-1 is present in pancreatic beta cells, SUR-2A – in cardiomyocytes, SUR-2B – in smooth muscle cells [3, 4]. It is the affinity with these receptors that determines the selectivity of the action of PSM drugs (Fig. 2).
Opening of KATP channels in cardiomyocytes protects the heart during ischemia. Sulfonylureas with affinity for KATP channels in cardiomyocytes can inhibit their opening. At the same time, PSMs with selectivity for SUR-1 are associated with lower cardiovascular risk [5] and are preferable, especially in individuals at high risk of developing myocardial ischemia.
A consequence of chronic hyperglycemia is oxidative stress, leading to apoptosis of pancreatic beta cells. Glibenclamide increases the formation of hydroxyl, peroxide and other radicals (reactive oxygen species), which enhance beta cell apoptosis [6].
The high selectivity and affinity of Diabeton MB and the ability to neutralize free radicals are explained by the presence of an aminoazobicyclooctane ring in its structure [7]. By neutralizing free radicals, the drug is able to protect pancreatic beta cells from apoptosis [8].
In clinical practice, what was said earlier is extremely important, especially considering the phenomenon of secondary resistance to sulfonylureas. Thus, when studying secondary resistance to PSM in 248 patients with type 2 diabetes, it was found that after five years the frequency was lower in the gliclazide group (7%) than in the glibenclamide (glyburide) (18%) and glipizide (26%) groups. [9]. According to the results of a retrospective observation, the use of Diabeton MB, unlike other PSMs, made it possible to delay the prescription of insulin for more than eight years [10].
Cardiovascular safety
In 2008, experts from the Food and Drug Administration put forward new requirements for drug registration, according to which excess cardiovascular risk associated with new glucose-lowering drugs should be excluded [11].
It should be noted that the role of PSM in the prevention of cardiovascular complications in patients with type 2 diabetes has been studied in a number of randomized controlled trials. They included patients with type 2 diabetes without cardiovascular risk, as well as with high and very high cardiovascular risk.
Thus, the UKPDS study, which has become a textbook study in terms of frequency of citations, was conducted in individuals with newly diagnosed type 2 diabetes. Its authors studied the effect of intensive glycemic control on the development of micro- and macrovascular complications [12, 13]. Study participants were randomized to either standard glycemic control with diet therapy or intensive glycemic control using PSM (chlorpropamide, glibenclamide, glipizide) or insulin. Insulin and PSM were comparable in reducing the risk of microvascular complications. However, none of the drugs had a statistically significant effect on the incidence of macrovascular diseases [12]. The study results also indicated that there was no increased risk of cardiovascular death in patients receiving PSM. Following completion of the ten-year randomized phase of the UKPDS study, patient follow-up continued. Ten years later, at the end of the extension phase of the study, it was found that in the group of intensive glycemic control with PSM or insulin, the risk of myocardial infarction was lower by 15%, microvascular disease by 24%, and death from any cause by 13% [14]. .
The TOSCA.IT study included patients with type 2 diabetes and low cardiovascular risk who were on metformin monotherapy and did not achieve target levels of carbohydrate metabolism. 3028 patients were randomized to pioglitazone or PSM (glibenclamide - 2%, glimepiride - 48%, gliclazide - 50%). The study authors assessed the long-term effectiveness of dual therapy (metformin and comparator) on cardiovascular events [15]. After five years, there was no significant difference between treatment groups in achieving the primary endpoint (death from any cause, first case of nonfatal myocardial infarction, nonfatal stroke, or emergency myocardial revascularization).
The large international multicenter randomized trial ADVANCE included patients with type 2 diabetes with a disease duration of an average of eight years [16]. The aim of the study was to prove the superiority of intensive glycemic control (HbA1c ≤ 6.5%) in reducing the risk of both micro- and macrovascular complications over standard treatment. 11,140 patients were randomized into two groups of glucose-lowering therapy. The first received gliclazide MB and any other hypoglycemic drug, the second received standard treatment (if necessary, any PSM could be added, but not gliclazide). The follow-up period averaged five years. The primary endpoint included macrovascular (myocardial infarction, stroke, or cardiovascular death) and microvascular events (retinopathy or nephropathy). The study results demonstrated that the intensive strategy resulted in safer improvements in microvascular outcomes (especially renal outcomes) and was not associated with increased mortality. The primary outcome was achieved in 18.1% of cases in the intensive control group and in 20.0% in the standard control group (p = 0.013). Intensive therapy did not significantly reduce the risk of macrovascular complications (hazard ratio (HR) 0.94, p = 0.32). Differences in the primary outcome were primarily due to fewer microvascular events, particularly diabetic nephropathy. The frequency of the latter decreased by approximately 20%. Thus, the ADVANCE study demonstrated the safety of Diabeton MB in patients with type 2 diabetes with high and very high cardiovascular risk [16]. The long-term cardiovascular safety of intensive care was noted in the ten-year extension phase of the ADVANCE-ON study. The results regarding the development of end-stage chronic renal failure deserve special attention. Thus, 29 such cases were recorded in the intensive therapy group, 53 in the standard group (OR 0.54, p
The Danish STENO-2 study included 160 patients with type 2 diabetes, microalbuminuria and high cardiovascular risk. They received either standard treatment or intensive treatment (metformin or gliclazide) to maintain HbA1c levels
Thus, the results of the ADVANCE and STENO-2 studies indicate the benefits of simultaneous intensive correction of several risk factors in patients with type 2 diabetes. However, they do not answer the question: which component was most beneficial in terms of reducing the incidence of complications?
Reviews and meta-analyses of controlled studies have also proven the cardiovascular safety of Diabeton MB and glimepiride compared with glibenclamide [22, 23].
Of no less interest is the cardiovascular safety of modern innovative oral hypoglycemic drugs: dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT-2) inhibitors. Their cardiovascular safety was assessed in five studies - three with DPP-4 inhibitors and two with SGLT-2 inhibitors. For saxagliptin (SAVOR-TIMI), sitagliptin (TECOS) and alogliptin (EXAMINE) [24–26], the rate of achievement of the primary endpoint was not significantly different from that of placebo. However, the incidence of hospitalization for heart failure in those receiving saxagliptin compared with those taking placebo was significantly increased, and a trend towards the same was noted in those taking alogliptin. Only in the sitagliptin group was it similar to the placebo group.
In the EMPA-REG OUTCOME and CANVAS studies, the SGLT-2 inhibitors empagliflozin and canagliflozin, in contrast to placebo, demonstrated a cardioprotective effect [27, 28]. However, it should be noted that canagliflozin significantly increased the risk of limb amputation.
In the above studies, in addition to the above drugs, patients received metformin (66.2–81.6%) and/or PSM (40.2–46.5%).
The CAROLINA trial is due to complete in 2021 and will provide data on cardiovascular outcomes with the use of PSM (glimepiride) and a DPP-4 inhibitor (linagliptin).
Efficiency in combination and monotherapy
Monotherapy with metformin does not always lead to achieving target levels of carbohydrate metabolism, and even when such goals are achieved, the result eludes over time. As a result, there is a need for combination therapy. A number of meta-analyses and reviews have examined the effectiveness of different classes of antidiabetic drugs in patients with type 2 diabetes with insufficient control of carbohydrate metabolism on the background of metformin. The data obtained indicate that there are no significant differences between different classes of drugs in terms of reducing HbA1c levels [29, 30]. However, according to a systematic review of 218 randomized clinical trials involving approximately 79 thousand patients, different classes of glucose-lowering drugs differ in terms of achieving HbAlc
When comparing the effectiveness in reducing HbA1c, no differences were found between PSM alone and placebo [29, 32]. At the same time, according to the results of a meta-analysis of randomized clinical trials, PSMs reduced HbA1c levels more significantly than DPP-4 inhibitors [33].
Determining the time of onset of type 2 diabetes is usually quite difficult. Therefore, it can be assumed that the effect of hyperglycemia on the body was long-lasting, especially in patients with initially high HbA1c levels. In this regard, the results of the double-blind randomized controlled clinical trial ADOPT involving 4360 patients are of particular interest [34]. It examined the effectiveness of rosiglitazone, metformin and glibenclamide as initial monotherapy in patients with newly diagnosed type 2 diabetes. After five years, the cumulative incidence of secondary treatment failure was 21% for metformin, 34% for glibenclamide, and 15% for rosiglitazone. In the ADVANCE study, the intensive treatment strategy using Diabeton MB was characterized by longer-term glycemic control (over five years) achieving HbA1c ≤ 6.5%. Moreover, four out of every five patients achieved an HbA1c level ≤ 7.0% [16].
A meta-analysis of eight randomized clinical trials assessed the effectiveness of PSM and DPP-4 inhibitors on HbA1c over a long period of time (26, 52 and up to 104 weeks) [35]. Compared with PSM, DPP-4 inhibitors were associated with a smaller reduction in HbA1c levels from weeks 24–28 to 104 (mean difference -0.16%, 95% confidence interval (CI) -0.21– -0 .11(p
The hypoglycemic effect of PSM (glimepiride and glipizide when added to metformin) was also compared with SGLT-2 inhibitors. Similar studies have not been conducted with gliclazide.
One such study included 1549 patients who received empagliflozin or glimepiride [39]. The difference in mean HbA1c levels from baseline was assessed after two years, although the study was designed to last four years. It was -0.11% (95% CI -0.19 to -0.02), p = 0.0153) in favor of empagliflozin. Another study assessed the effectiveness of dapagliflozin and glipizide in 814 patients with type 2 diabetes [40]. After four years, a persistent decrease in HbA1c levels was observed with dapagliflozin. The difference was -0.30% (95% CI -0.51– -0.09).
There was also evidence that there was no significant difference in the reduction of HbA1c between PSM and glitazone when added to metformin [15, 41].
Effect on body weight
Since the release of PSMs onto the pharmaceutical market, the issue of their effect on body weight has been actively discussed. It has been established that PSM monotherapy promotes an increase in body weight by 1.5–2.5 kg [42]. Similar results were recorded in the UKPDS study. Thus, in patients receiving PSM, body weight increased more in the first year of treatment than in those receiving diet therapy - chlorpropamide and glibenclamide +2.6 and +1.7 kg, respectively [12]. However, after a year, this trend was no longer observed, and after three to four years, body weight stabilized [43]. In the ADOPT study, body weight increased by 1.6 kg in the first year of glyburide monotherapy, but subsequently stabilized [33]. In the ADVANCE study, patients in the intensive glycemic control group increased on average only 0.7 kg during follow-up (p
Risk of hypoglycemia
Iatrogenic hypoglycemia is a serious obstacle to intensifying therapy for patients with type 2 diabetes. The peculiarities of the mechanism of action of PSM determine the need to take it into account.
The results of multicenter comparative studies indicate differences in the risk of hypoglycemia among different PSM drugs. This depends primarily on their selectivity and reversibility of binding to the SUR-1 receptor on pancreatic beta cells [45–47]. Long-acting sulfonylureas (glibenclamide and glimepiride) that form active metabolites increase the risk of prolonged and severe hypoglycemia, especially in elderly patients [48, 49]. The risk of hypoglycemia with the use of glipizide and gliclazide turned out to be significantly low, which is due to their ability to degrade to inactive metabolites.
In a number of meta-analyses that compared glibenclamide with other PSMs, treatment with glibenclamide recorded an increase in the RR of any episodes of hypoglycemia by 1.4 times, and of severe hypoglycemia by more than 4.7 times [46]. It was also found that with a comparable reduction in HbA1c levels (from -0.66 to -0.84%), the addition of gliclazide to metformin was associated with the lowest risk of hypoglycemia of any severity compared with the addition of glibenclamide (RR 0.40 (95% CI 0. 13–1.27)), glimepiride (RR 0.21 (95% CI 0.03–1.48)) and glipizide (RR 0.22 (95% CI 0.05–0.96)) [50] .
A meta-analysis of randomized clinical trials regarding the incidence of hypoglycemia with sulfonylurea drugs found that hypoglycemia with blood glucose levels ≤ 3.1 mmol/l was observed in 10.1% of patients receiving any drug of this class (95% CI 7. 3–13.8%), and only in 1.4% of patients receiving gliclazide (95% CI 0.8–2.4%) [47]. Severe hypoglycemia was recorded in 0.8% of patients receiving any PSM (95% CI 0.5–1.3%), and only 0.1% receiving gliclazide (95% CI 0.0–0.7%). The results of meta-analyses of randomized clinical trials confirmed a significantly lower risk of hypoglycemia in patients receiving gliclazide compared with patients taking other sulfonylureas (RR 0.47 (95% CI 0.77–0.70), p = 0.004) [32] .
In the GUIDE study, gliclazide MB and glimepiride were equally effective in improving blood glucose control, but the number of hypoglycemic episodes with the former was almost 50% less than with the latter [51].
In the ADVANCE trial, an intensive treatment strategy based on gliclazide MB, compared with standard therapy, was associated with a lower risk of severe hypoglycemia - one severe episode of hypoglycemia in 2.7% of patients versus 1.5% [16]. At the same time, in the ACCORD and VADT studies, the frequency of severe episodes of hypoglycemia in the intensive control groups was 16.2 and 21.2%, respectively [52, 53].
It has been established that during Ramadan the risk of episodes of severe hypoglycemia increases by 7.5 times [54, 55]. In 1024 individuals with type 2 diabetes who fasted during this period, the incidence of hypoglycemia during treatment with sulfonylureas - glibenclamide, glimepiride and gliclazide MB, as well as the DPP-4 inhibitor sitagliptin was 19.7, 12.4, 6.6 and 6.7 % respectively [56]. This indicates the safety of Diabeton MB even in comparison with a DPP-4 inhibitor. It should be noted that during fasting, glucose-lowering therapy should be carried out under careful glycemic control and in compliance with all medical recommendations [55–57].
Nephroprotection
Diabetes mellitus is the leading cause of end-stage chronic renal failure [58], so there is an urgent question about the acceptability of using drugs of one class or another for the treatment of patients with impaired renal function.
The use of most antidiabetic drugs is limited by glomerular filtration rate (GFR). The possibility of using PSM depends on the degree of kidney damage and the risk of developing hypoglycemic conditions [59]. Sulfonylureas, the breakdown of which is accompanied by the formation of active metabolites (glibenclamide, glimepiride), increase the risk of hypoglycemia as GFR decreases. Therefore, glibenclamide should preferably be prescribed only to patients with normal renal function or mild chronic renal failure (GFR 60–90 ml/min/1.73 m2); in those with GFR 30–60 ml/min/1.73 m2, it should be used with caution, and in persons with GFR 2 it should be discontinued. At the same time, glimepiride at a lower dose can be used when GFR is 30–60 ml/min/1.73 m2 [50]. Gliclazide and glipizide are broken down to inactive metabolites, and therefore the risk of hypoglycemia is low in patients with renal failure. These drugs can be used when GFR is less than 30 ml/min/1.73 m2, subject to careful monitoring of patients [60]. This is especially true for gliclazide, which, like DPP-4 inhibitors, can be used in the first to third stages of chronic kidney disease (GFR > 30 ml/min/1.73 m2), and in a reduced dose in patients with severe chronic kidney disease [50 , 61].
According to the research results, intensive glycemic control in the gliclazide MB group led to a reduction in the risk of microalbuminuria by 9% (p = 0.01), macroalbuminuria by 30% (p
When prescribing SGLT-2 inhibitors, it should be taken into account that their ability to block glucose reabsorption depends on adequate renal function, therefore they are contraindicated in patients with GFR 2.
The place of sulfonylurea derivatives in modern treatment algorithms
The results of systematic reviews and meta-analyses have contributed to the recognition of the glucose-lowering effectiveness of PSM.
In authoritative national and international guidelines, the effectiveness of metformin, PSM, glitazones and GLP-1 receptor agonists is characterized as high, compared with the intermediate effectiveness of DPP-4 inhibitors and SGLT-2 [63]. International guidelines updated in 2018, such as the American Diabetes Association Standards of Care, consider PSM as an adjunct to metformin in patients with cardiovascular disease after failure of drugs with proven benefits on cardiovascular risk. PSMs remain second-line drugs, provided they are added to metformin, in patients without cardiovascular disease [64–66].
In a number of national guidelines, PSM are differentiated depending on the class. In particular, experts from the Royal College of General Practitioners and Diabetologists of Australia, the Italian Society of Diabetology, and the Society of Endocrinology, Metabolism and Diabetes of South Africa identified gliclazide as a drug with a lower risk of developing cardiovascular diseases, hypoglycemia and weight-neutral [67–70 ].
The recommendations of the National Kidney Foundation Quality and Outcomes Action Group indicate that gliclazide MB 60 mg is the most preferred SAM in patients with chronic renal failure [71].
Experts from the World Health Organization (WHO) recommend the use of metformin and gliclazide MB in patients with type 2 diabetes in the indicative list of essential medicines [72]. It is important to recall that WHO (2018) recommendations are fundamental for most countries, where access and cost remain key factors in treatment decisions.
The Federation of South Asian Endocrine Societies consensus considers PSMs to be the preferred second-line treatment after metformin [73]. In the recommendations of the Canadian Diabetes Association (2013), gliclazide appears as the drug with the lowest incidence of hypoglycemia [74]. It is important to emphasize that in the most recent recommendations - a joint consensus of the European Association for the Study of Diabetes and the American Diabetes Association - PSMs are indicated as second-line drugs in patients without severe comorbid background, that is, without cardiovascular diseases of atherosclerotic origin or chronic renal failure.
Conclusion
The medical and social significance of type 2 diabetes determines the urgency of the issue of achieving glycemic targets. To achieve these, first of all, you should adhere to a personalized approach to treatment.
In all national and international treatment algorithms for patients with type 2 diabetes, the drug of first choice is metformin, provided it is well tolerated and there are no contraindications for use.
Currently, in Russia, seven classes of drugs, both oral and injectable, including innovative ones, are used to treat diabetes. Such a wide choice requires doctors to have deep knowledge and skills when developing treatment tactics.
Despite the introduction of innovative drugs into clinical practice, sulfonylurea derivatives retain their importance as second- and third-line drugs due to proven effectiveness and safety, extensive clinical experience in use, ease of use, the ability to combine them with other glucose-lowering drugs, and low cost.
Given that type 2 diabetes is the equivalent of cardiovascular pathology, in patients with established cardiovascular diseases, preference should be given to drugs with a proven positive effect on cardiovascular endpoints. Diabetes CF has been proven in many studies to be cardiac safe, nephroprotective, low risk of hypoglycemia and weight neutral.
