Galvus Met Tablets, box, 30 pcs, 50 + 1000 mg + mg, for oral administration
special instructions
In patients receiving insulin treatment, Galvus Met cannot replace insulin therapy. Vildagliptin Impaired liver function Since when using vildagliptin, an increase in aminotransferase activity (usually without clinical manifestations) was noted somewhat more often than in the control group, before using the drug Galvus Met, and also regularly during treatment with the drug, it is recommended to determine biochemical indicators of liver function. If an increase in aminotransferase activity is detected, a repeat study should be carried out to confirm the result, and then biochemical indicators of liver function should be regularly determined until they normalize. If the excess of AST or ALT activity by 3 or more times above the ULN is confirmed by repeated testing, it is recommended to discontinue the drug. Metformin Lactic acidosis Lactic acidosis is a very rare but severe metabolic complication that occurs when metformin accumulates in the body. Lactic acidosis during the use of metformin was observed mainly in patients with diabetes mellitus with severe renal impairment. The risk of developing lactic acidosis increases in patients with diabetes mellitus that is difficult to treat, with ketoacidosis, prolonged fasting, prolonged alcohol abuse, impaired liver function and diseases that cause hypoxia. With the development of lactic acidosis, shortness of breath, abdominal pain and hypothermia are noted, followed by coma. The following laboratory parameters have diagnostic value: a decrease in blood pH, a lactate concentration in the blood serum above 5 nmol/l, as well as an increased anion gap and an increase in the lactate/pyruvate ratio. If lactic acidosis is suspected, the drug should be discontinued and the patient should be hospitalized immediately. Monitoring renal function Since metformin is largely eliminated by the kidneys, the risk of its accumulation with the development of lactic acidosis increases in proportion to the severity of renal impairment. When using the drug Galvus Met, renal function should be regularly assessed, especially in conditions that contribute to its impairment, such as the initial phase of treatment with antihypertensive drugs, hypoglycemic agents or NSAIDs. Renal function should be assessed before starting treatment with Galvus Met, and then at least once a year in patients with normal renal function and at least 24 times a year in patients with CK at the lower limit of normal, as well as in elderly patients. In patients at high risk of developing renal impairment, monitoring should be carried out more often than 2-4 times a year. If signs of deterioration in renal function appear, Galvus Met should be discontinued. Use of iodine-containing X-ray contrast agents for intravascular administration When conducting x-ray studies that require intravascular administration of iodine-containing X-ray contrast agents, taking the drug Galvus Met should be temporarily discontinued (no later than 48 hours before, as well as within 48 hours after the study), since intravascular administration of iodine-containing X-ray contrast agents can lead to a sharp deterioration in kidney function and increase the risk of developing lactic acidosis. Galvus Met should be resumed only after renal function has been re-evaluated. Hypoxia In acute cardiovascular failure (shock), acute heart failure, acute myocardial infarction and other conditions characterized by hypoxia, lactic acidosis and prerenal acute renal failure may develop. If the above conditions occur, the drug should be discontinued immediately. Surgical interventions During surgical interventions (with the exception of minor operations not related to restriction of food and liquid intake), the drug Galvus Met should be discontinued. Resumption of the drug is possible after restoration of oral food intake in patients with renal impairment reliably excluded. Alcohol consumption It has been established that ethanol enhances the effect of metformin on lactate metabolism. Patients should be warned against alcohol abuse while using Galvus Met. Vitamin B12 content It has been established that metformin causes an asymptomatic decrease in the concentration of vitamin B12 in the blood serum in approximately 7% of cases. Such a decrease in very rare cases leads to the development of anemia. After discontinuation of metformin and/or vitamin B12 replacement therapy, serum vitamin B12 concentrations rapidly return to normal. In patients receiving Galvus Met, general clinical blood test parameters should be monitored at least once a year. If deviations of hematological parameters from the norm are detected, the etiology of such disorders should be clarified and appropriate treatment should be carried out. Some patients (eg, patients with insufficient intake or malabsorption of vitamin B12 or calcium) are predisposed to decreased serum concentrations of vitamin B12. In such patients, determining the concentration of vitamin B12 in the blood serum at least once every 2-3 years can have diagnostic value. Deterioration of the condition of patients with type 2 diabetes mellitus who previously responded to therapy. When detecting deviations in laboratory parameters from the norm or when clinical symptoms of a deterioration in the general condition appear (especially if the symptoms are unclear and vague) in patients with a previous adequate response to therapy, laboratory diagnostics should be immediately performed to detection of ketoacidosis and/or lactic acidosis. If acidosis is detected, you should immediately stop using the drug and take the necessary measures to correct the patient’s condition. Hypoglycemia As a rule, hypoglycemia is not observed in patients receiving therapy only with Galvus Met, but it can occur against the background of a low-calorie diet (when intense physical activity is not compensated for by the caloric content of food), or against the background of alcohol consumption. The development of hypoglycemia is most likely in elderly, weakened or malnourished patients, as well as against the background of hypopituitarism, adrenal insufficiency or alcohol intoxication. In elderly patients and in those receiving beta-blockers, the diagnosis of hypoglycemia may be difficult. Reduced effectiveness of hypoglycemic agents When stress (fever, injury, infection, surgery, etc.) develops in patients receiving hypoglycemic agents according to the standard regimen, a sharp decrease in the effectiveness of the latter for some time is possible. In this case, it may be necessary to temporarily discontinue Galvus Met and insulin therapy. Resumption of treatment with Galvus Met is possible after the end of the acute period. Fertility: In experimental studies in animals, the use of vildagliptin in doses 200 times higher than recommended did not cause fertility problems. There were no adverse effects on fertility in males or females when metformin was administered at doses of 600 mg/kg per day, which is approximately 3 times the recommended human dose (based on body surface area). There have been no studies of the effect on fertility in humans. Effect on the ability to drive vehicles and operate machinery The effect of the drug Galvus Met on the ability to drive vehicles and operate machinery has not been studied. If dizziness develops while using the drug, you should refrain from driving vehicles and machinery.
Galvus Met®
In patients receiving insulin treatment, Galvus Met® cannot replace insulin therapy. Galvus Met® should not be used to treat type 1 diabetes or diabetic ketoacidosis.
Vildagliptin
Liver dysfunction
The use of the combination drug vildagliptin + metformin is not recommended for patients with clinical or laboratory signs of liver dysfunction, including patients with an increase in ALT or AST >3 x ULN before treatment.
Rare cases of liver dysfunction (including hepatitis) have been reported with the use of vildagliptin. These cases were usually asymptomatic, without clinical consequences, and after discontinuation of therapy, liver function tests returned to normal. Liver function should be examined before starting therapy with the combination drug vildagliptin + metformin, then monitored once every 3 months during the first year of use of the drug, and then periodically. If an increase in aminotransferase activity is detected, a re-examination should be carried out to confirm the result, and then biochemical indicators of liver function should be regularly determined until they normalize. If an excess of AST or ALT activity of 3 or more times the ULN is confirmed upon re-examination, the use of the drug should be discontinued. If jaundice or other signs of liver dysfunction develop while using the vildagliptin + metformin combination, therapy should be discontinued immediately. After normalization of liver function indicators, treatment with the drug cannot be resumed.
Metformin
Lactic acidosis
Lactic acidosis is a very rare but severe metabolic complication, most often occurring with a sharp deterioration in renal function, as well as with cardiorespiratory syndromes and sepsis. With a sharp deterioration in kidney function, metformin accumulates in the body, which increases the risk of developing lactic acidosis.
If dehydration occurs (eg, associated with severe diarrhea or vomiting, fever, or decreased fluid intake), a patient taking metformin-containing medications (eg, Galvus Met®) should immediately stop taking the above medications and seek medical attention.
In patients taking drugs containing metformin (for example, Galvus Met®), caution should be exercised when initiating therapy with drugs that can acutely worsen renal function (for example, antihypertensive drugs, diuretics, NSAIDs). Other risk factors include: alcohol abuse, liver dysfunction, inadequately controlled diabetes mellitus, ketoacidosis, prolonged fasting, conditions associated with hypoxia, and concomitant use of drugs that can cause lactic acidosis.
Diagnosis of lactic acidosis
The patient and/or caregivers should be informed of the risk of developing lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. If symptoms develop that suggest the development of lactic acidosis, the patient should stop taking metformin-containing drugs (for example, Galvus Met®) and immediately seek medical help. Laboratory and instrumental examination data: decreased blood pH (<7.35), increased lactate concentration in the blood serum >5 mmol/l, as well as an increased anion gap and an increase in the lactate/pyruvate ratio. If lactic acidosis is suspected, therapy with metformin-containing drugs should be stopped and the patient should be hospitalized immediately.
Monitoring kidney function
Before starting therapy, GFR should be determined, and this indicator should be monitored periodically during drug therapy. The use of metformin-containing drugs (such as Galvus Met®) is contraindicated in patients with GFR <30 ml/min; in the presence of conditions that can impair renal function, the use of the above drugs should be temporarily suspended.
Since metformin is largely eliminated by the kidneys, the risk of accumulation and development of lactic acidosis increases with the severity of renal impairment. Because older age may be associated with deterioration of renal function, in patients in this category the dose of metformin-containing drugs (such as Galvus Met®) should be carefully adjusted to select the minimum dose that provides adequate glycemic effect, with regular monitoring of renal function.
Interactions
Concomitant use of medications that affect renal function or the distribution of metformin
Caution should be exercised when used concomitantly with drugs that can affect renal function, have significant hemodynamic effects or affect the distribution of metformin in the body, such as organic cations excreted by the kidneys by tubular secretion.
The use of iodine-containing radiocontrast agents for intravascular administration
Intravenous administration of radiopaque iodine-containing agents can provoke the development of contrast-induced nephropathy, leading to the accumulation of metformin in the body and increasing the risk of developing lactic acidosis. Metformin-containing medications (such as Galvus Met®) should be temporarily discontinued before or during the procedure; Dosage should be resumed no earlier than 48 hours after the procedure, after receiving laboratory confirmation of stabilization of renal function.
Alcohol consumption
It has been established that ethanol enhances the effect of metformin on lactate metabolism. The patient should be warned not to abuse alcohol while using metformin-containing drugs (such as Galvus Met®).
Alcohol intoxication is associated with an increased risk of lactic acidosis, especially with prolonged fasting, malnutrition and impaired liver function.
Vitamin B12 content
It has been established that metformin causes an asymptomatic decrease in the concentration of vitamin B12 in the blood serum in approximately 7% of cases. Such a decrease in very rare cases leads to the development of anemia. After discontinuation of metformin and/or vitamin B12 replacement therapy, serum concentrations of vitamin B12 quickly normalize. In patients receiving metformin-containing drugs (such as Galvus Met®), general clinical blood test parameters should be monitored at least once a year. If deviations of hematological parameters from the norm are detected, the etiology of such disorders should be clarified and appropriate treatment should be carried out. Some patients (eg, patients with insufficient intake or malabsorption of vitamin B12 or calcium) are predisposed to decreased serum concentrations of vitamin B12. In such patients, determining the concentration of vitamin B12 in the blood serum at least once every 2-3 years can have diagnostic value.
Hypoxia
Cardiovascular collapse (shock), acute heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia are associated with lactic acidosis and may also contribute to prerenal azotemia. If the above conditions occur, the use of metformin-containing drugs (such as Galvus Met®) should be stopped immediately.
Surgical interventions
During surgical procedures under general, spinal or epidural anesthesia (except for minor operations not associated with restriction of food and fluid intake), the use of metformin-containing drugs (such as Galvus Met®) should be discontinued.
Resumption of the drug is possible no earlier than 48 hours after the intervention or after the restoration of oral food intake after receiving laboratory confirmation of stabilization of renal function.
Patients with liver dysfunction
Since lactic acidosis, which is one of the HPs of metformin, has been reported in some cases in patients with impaired liver function, the combination drug vildagliptin + metformin should not be used in patients with liver disease or impaired biochemical parameters of liver function.
Deterioration of the condition of patients with type 2 diabetes who previously responded to therapy
If a deviation in laboratory parameters from the norm is detected or clinical symptoms of a deterioration in the general condition appear (especially when symptoms are not clearly expressed and blurred) in patients with a previous adequate response to therapy, laboratory diagnostics should be immediately carried out to identify ketoacidosis and/or lactic acidosis. If acidosis is detected, you should immediately stop using the drug and take the necessary measures to correct the patient’s condition.
Hypoglycemia
As a rule, hypoglycemia is not observed in patients receiving therapy only with the combination drug vildagliptin + metformin, but it can occur against the background of a low-calorie diet (when intense physical activity is not compensated for by the caloric content of food), or against the background of alcohol consumption. The development of hypoglycemia is most likely in elderly, weakened or malnourished patients, as well as against the background of hypopituitarism, adrenal insufficiency or alcohol intoxication. In elderly patients and in those receiving beta-blockers, the diagnosis of hypoglycemia may be difficult.
Reduced effectiveness of hypoglycemic drugs
In case of stress (fever, injury, infection, surgery, etc.) that develops in patients receiving hypoglycemic drugs according to the standard regimen, a sharp decrease in the effectiveness of the latter for some time is possible. In this case, it may be necessary to temporarily discontinue therapy with the vildagliptin + metformin combination and transfer to insulin therapy. Resumption of treatment with Galvus Met® is possible after the end of the acute period.
Fertility
There have been no studies of the effect of the combination drug vildagliptin + metformin on fertility in humans. In animal studies, vildagliptin at doses 200 times higher than recommended did not cause fertility problems.
There were no adverse effects on fertility in males or females when metformin was administered at doses of 600 mg/kg per day, which is approximately 3 times the recommended human dose (based on body surface area).
Instructions for use GALVUSMET®
Suction
Galvusmet
In a bioequivalence study, Galvusmet tablets of different concentrations (50 mg/500 mg, 50 mg/850 mg and 50 mg/1000 mg) were compared with a combination of the individual drugs vildagliptin and metformin hydrochloride at corresponding doses. These studies demonstrated the bioequivalence of Galvusmet in combinations of individual drugs in terms of AUC and Cmax of both components of Galvusmet - vildagliptin and metformin hydrochloride.
Food intake does not affect the volume and extent of absorption of vildagliptin in Galvusmet. Cmax and AUC of metformin hydrochloride when taken with food decreased by 26% and 7%, respectively. The absorption of metformin hydrochloride was also delayed when taking the drug with food, which was reflected in Tmax (from 2.0 to 4.0 hours).
These changes in Cmax and AUC were consistent but less than those observed when metformin hydrochloride was taken alone with food. The effect of food intake on the pharmacokinetics of both components of the drug - vildagliptin and metformin hydrochloride - is similar to the effect on the pharmacokinetics of vildagliptin and metformin hydrochloride when used individually with food.
Vildagliptin
After oral administration on an empty stomach, vildagliptin is rapidly absorbed, Cmax in blood plasma is reached after 1.75 hours. Administration with food slightly reduces the degree of absorption of vildagliptin, which is characterized by a decrease in Cmax by 19%, and also delays the time to reach Cmax in blood plasma to 2.5 hours. Volume of absorption did not change, food did not affect exposure at all (AUC).
Metformin hydrochloride
The absolute bioavailability of metformin hydrochloride 500 mg tablets taken on an empty stomach is approximately 50% to 60%. Studies of single oral administration of metformin hydrochloride, tablets 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate no dose-response relationship, which is due to decreased absorption rather than changes in elimination. Eating reduces the volume and slightly slows down the absorption of metformin hydrochloride, as evidenced by an approximately 40% lower mean Cmax, a 25% lower AUC, and a 35-minute increase in the time to reach Cmax after a single dose of 850 mg metformin hydrochloride with food. compared with the results after taking 850 mg of metformin hydrochloride on an empty stomach. The clinical significance of this decrease is unknown.
Linearity
Vildagliptin is rapidly absorbed, with absolute bioavailability after oral administration of 85%. Vildagliptin peak plasma concentrations and AUC increase over the therapeutic dose range in an approximately dose-dependent manner.
Distribution
Vildagliptin
The binding of vildagliptin to plasma proteins is low (9.3%); Vildagliptin is distributed equally between plasma and red blood cells. The average Vd of vildagliptin in the stationary phase after intravenous administration is 71 L, indicating extravascular distribution.
Metformin hydrochloride
The apparent Vd of metformin hydrochloride after a single oral dose of 850 mg averaged 654±358 L. Metformin hydrochloride is very little bound to plasma proteins, in contrast to sulfourea, which is more than 90% bound to plasma proteins. Metformin hydrochloride is distributed among red blood cells, most likely as a function of time. When using usual clinical doses and dosing regimens, steady-state plasma concentrations of metformin hydrochloride are achieved within 24 to 48 hours and are <1 mcg/ml. During controlled clinical trials of metformin hydrochloride, maximum plasma concentrations did not exceed 5 mcg/ml, even at the highest doses.
Metabolism
Vildagliptin
Metabolism is the major route of elimination of vildagliptin in humans, accounting for 69% of the dose. The main metabolite LAY151 is pharmacologically inactive and is a product of hydrolysis of the cyanogen fragment, accounting for 57% of the dose; followed by the hydrolysis product of the amide fragment (4% of the dose). DPP-4 is partially involved in the hydrolysis of vildagliptin.
Vildagliptin is not metabolized by cytochrome P450 enzymes to detectable amounts. In vitro studies have shown that vildagliptin does not inhibit or induce cytochrome P450 enzymes.
Removal
Vildagliptin
Following oral administration of 14C-vildagliptin, approximately 85% of the dose is excreted in the urine and 15% of the dose is excreted in the feces. After oral administration, 23% of the dose is excreted in the urine as unchanged vildagliptin. After intravenous administration to healthy volunteers, the total plasma clearance and renal clearance of vildagliptin are 41 L/h and 13 L/h, respectively.
The average T1/2 after intravenous administration is approximately 2 hours. T1/2 after oral administration is approximately 3 hours and does not depend on the dose.
Metformin hydrochloride
Studies using a single IV dose in healthy volunteers have shown that metformin hydrochloride is excreted unchanged in the urine and is not metabolized by the liver (no metabolites have been identified in humans) or excreted in the bile. Renal clearance is approximately 3.5 times higher than CC, which indicates tubular secretion as the main route of elimination.
After oral administration, approximately 90% of the absorbed drug is excreted by the kidneys within the first 24 hours, with a T1/2 from blood plasma of approximately 6.2 hours. In the blood, T1/2 is approximately 17.6 hours; this indicates that red blood cells may be a distribution compartment.
Pharmacokinetics in special groups of patients
Floor
No differences were observed in the pharmacokinetic parameters of vildagliptin or metformin hydrochloride
in men and women with different age ranges and body mass index.
Obesity
Body mass index has no effect on the pharmacokinetic parameters of vildagliptin
.
Liver failure
Exposure to vildagliptin
(100 mg) after a single dose in patients with mild and moderate hepatic impairment was reduced (20% and 8%, respectively), whereas vildagliptin exposure in patients with severe impairment increased by 22%. The maximum change (increase or decrease) in vildagliptin exposure is approximately 30%, which is not considered to be of clinical significance. There is no correlation between the severity of hepatic impairment and changes in vildagliptin exposure.
No pharmacokinetic studies have been performed on metformin hydrochloride.
in patients with liver failure.
Kidney failure
In patients with mild, moderate and severe renal impairment, as well as in patients with chronic renal failure who are on hemodialysis, systemic exposure to vildagliptin
increased (Cmax - from 8% to 66%; AUC - from 32% to 134%) compared with healthy volunteers.
Exposure to the inactive metabolite (LAY151) increased with increasing severity of renal failure (AUC 1.6-fold to 6.7-fold). Changes in vildagliptin exposure did not correlate with the severity of renal impairment, whereas changes in exposure to the inactive metabolite did.
T1/2 of vildagliptin did not change in renal failure. Based on the evaluation of the safety, tolerability and efficacy of vildagliptin in patients who participated in clinical trials with glomerular filtration values <60 ml/min, there is no need for dosage adjustment in patients with mild or moderate renal impairment. The use of vildagliptin is not recommended in patients with severe renal impairment or in patients with chronic renal failure who are on hemodialysis.
In patients with reduced renal function (based on determined QC) T1/2 of metformin hydrochloride
in plasma and blood is prolonged, and renal clearance decreases in proportion to the decrease in CC.
Elderly patients
In healthy elderly volunteers (>70 years), total exposure to vildagliptin
(100 mg 1 time/day) decreased by 32% with an 18% increase in Cmax in blood plasma compared with young healthy volunteers (aged 18 to 40 years). These differences are not considered clinically significant. Age-specific studies have shown that age does not affect DPP-4 inhibition by vildagliptin.
Limited data from controlled pharmacokinetic studies of metformin hydrochloride
in healthy elderly volunteers, indicate that the overall clearance of metformin hydrochloride from blood plasma is reduced, T1/2 is prolonged, and Cmax is increased compared to young volunteers. These data indicate that changes in the pharmacokinetics of metformin hydrochloride with age are mainly explained by changes in renal function.
Treatment with Galvusmet should not be initiated in patients aged >80 years unless CC determinations demonstrate no decline in renal function.
Children
No pharmacokinetic data available.
Ethnic groups
There is no evidence of an effect of ethnicity on the pharmacokinetics of vildagliptin or metformin hydrochloride.
Type 2 diabetes mellitus (T2DM) in the elderly population is a serious economic and medical problem, including due to the growing number of this group of patients worldwide [1, 2]. An aging population plays a leading role in the diabetes pandemic, along with obesity and sedentary lifestyles. The prevalence of T2DM increases with age, reaching 20% in the group of people over 70 years of age. Half of patients with T2DM are over 65 years of age [3]. An increased prevalence of cardiovascular risk factors is also common in the elderly. In addition, this group typically experiences high morbidity and mortality due to renal dysfunction, congestive heart failure, psychological and psychiatric disorders, physical inactivity, weakness, and vulnerability [3]. Older people usually take multiple medications, which increases the risk of drug interactions and the development of side effects, including severe hypoglycemia when using antidiabetic drugs [4]. Thus, the management of T2DM among elderly and very elderly patients is quite challenging.
Treatment of elderly patients with T2DM is also complicated by the lack of data from prospective clinical studies on the choice of treatment algorithm and setting therapeutic goals in this population. It should be noted that data from a group of younger patients cannot be automatically transferred to older patients. Moreover, elderly patients represent a fairly heterogeneous group in terms of duration of diabetes, general status, presence of concomitant diseases and therapy. In other words, there are many prerequisites for the development of individualized approaches to the treatment of such patients [5].
The risk of hypoglycemia is probably the factor that most complicates treatment in older people [7]. Hypoglycemia is especially dangerous and has severe consequences for elderly patients who have lost the ability to recognize symptoms indicating their approach [6, 7]. Problems with comorbidities, combined with the risk of hypoglycemia, significantly limit the choice of therapeutic options for the elderly patient population. Recently, interesting data have emerged suggesting that the use of drugs that increase the activity of incretins may provide significant benefits to elderly patients with T2DM, taking into account their glucose-dependent mechanism of action, low risk of hypoglycemia and effective improvement of glycemic control with minimal risk of side effects [ 9]. Drugs in this group improve the sensitivity of α and β cells to glucose by increasing and prolonging the activity of glucagon-like peptide-1 (GLP-1), which in turn modulates the glucose-dependent secretion of insulin and glucagon, maintaining blood sugar levels within physiological limits without increasing the frequency of hypoglycemia.
Features of T2DM in elderly patients. Higher risk and more severe consequences of hypoglycemia
Hypoglycemia is the most common side effect of therapy with antidiabetic drugs, which increase insulin levels independently of blood glucose levels. These drugs include insulin secretagogues, including sulfonylurea derivatives and glinides, as well as insulin preparations. The actual incidence of hypoglycemia is often underestimated because many episodes remain unrecognized [6]. It is known that the frequency of hypoglycemia significantly increases with age, but its actual prevalence in the population of elderly patients is even more difficult to estimate [6, 7]. Indeed, older people who do not have sufficient knowledge about hypoglycemia often incorrectly assess their condition, which leads to an underestimation of the frequency of hypoglycemia [7].
This situation is aggravated by the presence in many elderly patients of cognitive impairment and disorientation, which can be mistaken for hypoglycemia [7]. In such patients, age-related impairment of the ability to recognize oncoming symptoms progresses, and accordingly, the ability to take preventive or therapeutic measures decreases [8]. The consequences of hypoglycemia in the elderly can be significantly more severe compared to the general population. In this case, behavioral disorders are often a consequence of hypoglycemia. Severe episodes of hypoglycemia in such patients can cause hospitalization for fractures after falls and are associated with the development of acute renal failure and severe cardiovascular accidents with high mortality. Patient age was identified as a significant predictor of hypoglycemia requiring medical attention in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study, which showed a 3% increase in risk with each additional year of life (p < 0.0001) [10] .
Data from the VADT (Veterans Affairs Diabetes Trial) and ACCORD studies evaluating intensive and standard treatment regimens for T2DM emphasize the need to avoid hypoglycemia during treatment [11]. The VADT study showed that a severe episode of hypoglycemia significantly increased the risk of cardiovascular mortality during 3 months of therapy. The ACCORD study found no difference between mortality rates in the intensive and conventional therapy groups. Moreover, the frequency of severe hypoglycemia was associated with a significant increase in mortality, regardless of the intensity of therapy [11].
Data from a study of a cohort that included 16 thousand patients with T2DM from Northern California showed that in elderly patients, a history of 3 severe episodes of hypoglycemia significantly increases the risk of developing dementia [12].
Thus, when treating elderly patients with T2DM, it is always necessary to remember that for them hypoglycemia is associated with a high risk of developing severe complications.
High prevalence of micro- and macrovascular complications and increased risk of functional impairment, including cognitive impairment, in older patients with T2DM
T2DM is associated with the progressive development of micro- and macrovascular complications, the prevalence of which increases with age [4–7], and remains the main cause of mortality and reduced life expectancy in elderly patients [3]. However, in addition to the traditional late complications of diabetes, which are widespread in older patients, this population is at increased risk of developing other equally severe clinical syndromes, such as functional impairment, physical limitations, falls, fractures, cognitive impairment, and depression [3]. Functional disorders are characterized by difficulties in performing routine physical work, which significantly affects the outcome of treatment and the quality of life of patients [3, 4]. With age, patients with T2DM have a higher risk of developing cognitive impairment. In a study by M. Munshi et al. [20] showed that every third patient with T2DM over 70 years of age suffers from intellectual impairment. Depression also often accompanies the course of T2DM and can increase the manifestations of cognitive dissonance, especially with unsatisfactory metabolic control [5, 20].
Heterogeneity of diabetes. the need to select treatment goals in accordance with the functional status
The population of elderly patients with T2DM is a heterogeneous group in terms of duration of diabetes, life expectancy, and the presence of concomitant diseases. The goals of therapy may differ significantly among them, for example, in patients with long-term diabetes and multiple comorbidities compared with patients with recently developed T2DM and generally in good health [5, 12].
It has now been proven that early intensive therapy with strict control goals subsequently provides the so-called. metabolic memory effect. This is shown in a report on a 10-year follow-up of a cohort of patients after completion of the UKPDS (UK Prospective Diabetes Study). In older patients with newly diagnosed T2DM, stricter control goals provided greater benefits, including improvements in cognitive function [10] and overall health. At the same time, for patients with long-term diabetes, a more gentle approach when choosing goals for glycemic control is rational. Currently, the European Society for the Control of Older People with Diabetes recommends flexible treatment goals of a glycated hemoglobin (HbA1c) level of up to 8%, with a particular emphasis on their quality of life, minimizing the risk of hypoglycaemia and other side effects of therapy.
Therapy using incretin drugs in elderly patients with T2DM
Incretins - GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) - are short-acting hormones secreted in the intestine in response to food intake. They provide the first phase of insulin secretion and coordinate the function of islet cells. Of particular importance is the ability of incretins to control the secretion of glucagon by α-cells, as well as the experimentally proven ability to suppress apoptosis and preserve the function of β-cells [13].
Therapy based on incretins (DPP-4 inhibitors and GLP-1 analogues) provides glucose-sensitive modulation of insulin and glucagon secretion. This minimizes the risk of hypoglycemia and maintains glycemic control within physiological limits, in contrast to the use of sulfonylureas and glinides. Such possibilities are of particular interest in the treatment of elderly patients with T2DM [13, 14].
Unlike GLP-1 receptor agonists, DPP-4 inhibitors are taken orally. They enhance and prolong the action of endogenous incretins in physiological concentrations. Therapy with DPP-4 inhibitors is associated with a minimal risk of hypoglycemia and does not cause weight gain [13–15]. Unlike GLP-1 analogues, DPP-4 inhibitors do not slow down the rate of gastric emptying without causing gastrointestinal side effects. Currently, the following DPP-4 inhibitors are used in the treatment of T2DM: vildagliptin (Galvus), sitagliptin (Januvia) and saxagliptin (Ongliza). Several more inhibitors are under development (alogliptin, linagliptin, etc.). Vildagliptin is currently used in 75 countries around the world.
Data on the pharmacokinetics of vildagliptin showed that the patient’s age does not affect its properties and parameters of elimination from the body [13]. Vildagliptin breaks down by hydrolysis into pharmacologically inactive metabolites. The primary route of elimination is the kidneys: 85% of the administered dose is excreted in the urine in the form of inactive components [13, 14]. Vildagliptin is not currently approved for use in patients with glomerular filtration rate (GFR) below 50 mL/min, and no dose adjustment is required if GFR is above this level. Two large clinical trials are currently underway to evaluate the long-term safety of vildagliptin in patients with moderate to severe renal impairment. The drug is not metabolized through the cytochrome system (CYP450) and does not interact with drugs that are most often used in the treatment of elderly patients [14]. In addition, vildagliptin does not bind to plasma proteins, which also reduces the risk of drug-drug interactions [13].
Clinical data on the use of vildagliptin in a population of elderly patients with T2DM
A large clinical trial program for vildagliptin was conducted to evaluate the treatment of elderly patients with T2DM. This made it possible to conduct an expanded analysis in the group of patients over 65 years of age (374 people) and over 75 years of age (1890 people). All patients initially had cardiovascular risk factors and numerous concomitant diseases, for which intensive drug therapy was carried out. A subgroup of older patients had lower HbA1c, fasting blood glucose (FBG) and body weight compared to younger patients. Treatment with vildagliptin (50 mg twice daily) for 24 weeks led to a significant improvement in glycemic control with a decrease in HbA1c and BGL levels in both individuals over 75 years of age (by 1.2% and 1.5 mmol/L, respectively) and in younger patients (by 0.9% and 1.1 mmol/l) [16].
In addition, this improvement in carbohydrate metabolism was accompanied by a slight decrease in body weight (0.9 kg in patients over 75 years of age and 0.2 kg in those under 75 years of age).
The therapy was well tolerated by all patients and was not accompanied by significant side effects. In patients over 75 years of age with mild renal failure, there was no increase in the incidence of side effects of therapy compared with a similar group of patients under 75 years of age and without impaired renal function. In the group of patients over 75 years of age, there were practically no confirmed episodes of hypoglycemia (0.8%), as well as in the group of patients under 75 years of age (0%; see table). The data obtained allowed us to obtain approval for the use of vildagliptin in the population of elderly patients.
. Frequency of hypoglycemia during monotherapy with vildagliptin and in combination with other oral hypoglycemic drugs.
The data presented above were confirmed in randomized, double-blind studies comparing therapy with vildagliptin (50 mg twice daily) or metformin (1500 mg/day) conducted for 6 months in 335 patients with T2DM over 65 years of age who had not previously received treatment [15 ]. The average age of the patients was 71 years (65–93 years), the initial HbA1c level was 7.7%, and the body mass index was 29.6 kg/m2. Of the study participants, 92% of patients received concomitant therapy, 50% had mild renal failure (GFR-50–80 ml/min/1.73 m2). After 6 months of treatment, HbA1c levels decreased approximately to the same extent during therapy with vildagliptin (by 0.64%) and metformin (by 0.75%). Mean HbA1c values at 6 months were 7.1 and 7.0% on vildagliptin and metformin therapy, respectively. Despite improved control of T2DM, not a single episode of hypoglycemia was recorded in the vildagliptin therapy group and only 2 (1.2%) episodes in the metformin group. Treatment with vildagliptin was associated with a lower incidence of adverse events (44.3 versus 50.3%) and discontinuation of therapy (4.2 versus 7.9%) compared to metformin. Treatment discontinuations were primarily due to gastrointestinal side effects (diarrhea incidence was 3.0% with vildagliptin and 24.3% with metformin).
Recently, the results of another study evaluating vildagliptin therapy in patients with T2DM over the age of 75 years were published [21]. The results of this analysis demonstrated the effectiveness and good tolerability of vildagliptin in patients who averaged 77 years of age. These patients had a lower degree of obesity compared to younger ones (body mass index - 29.4 and 31.5 kg/m2, respectively) and a higher frequency of concomitant diseases (30% had a history of cardiovascular diseases, 70% had a history of renal disease). failure). Vildagliptin therapy provided a reduction in HbA1c levels by 0.9% (initial 8.3%) in monotherapy and by 1.1% (initial 8.5%) in combination with metformin. This improvement was comparable to the dynamics of glycemia in patients under 75 years of age. No hypoglycemic episodes were recorded. The overall incidence of adverse events and the incidence of serious adverse events were low and comparable in the group of patients older and younger than 75 years.
Data on the minimal risk of hypoglycemia among elderly patients receiving vildagliptin therapy were confirmed in another study that included patients over 65 years of age (144 people) with a short duration of T2DM (initial mean HbA1c level = 6.7%). During two years of therapy (one year of follow-up and one year of extended follow-up), no patients in the vildagliptin group reported episodes of hypoglycemia, despite improved glycemic control compared with placebo (a significant difference in HbA1c levels after 2 years of therapy was 0.5%) [ 17].
Another study of adding vildagliptin to insulin therapy included 296 patients with T2DM, one third of whom were over 65 years of age (mean age 71 years) [18]. The duration of the disease was 18 years, of which for the last 7 years patients received insulin (average dose - 66 U/day, initial HbA1c level = 8.4%). After 6 months of therapy in the group of elderly patients, the HbA1c level decreased by 0.7% from baseline (p < 0.001 compared with placebo), and the addition of vildagliptin was accompanied by a decrease in the frequency of hypoglycemia compared with placebo: in 13% of patients in the vildagliptin + insulin group compared with 26% in the placebo + insulin group [18]. In a double-blind extended observation period, HbA1c levels decreased by 0.9% from baseline after a year of therapy with vildagliptin (50 mg twice daily; Fig. 1) [19].
A study of the effectiveness of the combination of vildagliptin + metformin compared with the combination of glimepiride + metformin showed a 10-fold reduction in the risk of hypoglycemia in a subgroup of 172 patients with T2DM aged 65 years [19]. After a year of observation, improvement in glycemic control was noted with both treatment options. But the overall incidence of hypoglycemia was 1.4% in the vildagliptin group versus 15.6% in the glimepiride group. The advantage of vildagliptin was confirmed after a year of extended follow-up: in elderly patients, the incidence of hypoglycemia with its use was 2.1 versus 17.5% during therapy with glimepiride (p < 0.001; Fig. 2).
The low incidence of hypoglycemia during vildagliptin therapy can be explained by improved counterregulation of insulin secretion. Data have been published that, under conditions of a hyperinsulinemic hypoglycemic clamp, vildagliptin significantly increases glucagon levels compared to placebo (by 38%), thereby improving the sensitivity and response of β-cells to stimulation in a state of hypoglycemia [14].
Conclusion
Elderly patients with T2DM are most susceptible to the negative effects of hypoglycemia. They have a significantly reduced ability to recognize the onset of hypoglycemia, which leads to more severe and prolonged episodes with significant complications. Studies in older patients with T2DM have shown that the use of DPP-4 inhibitors is beneficial in the treatment of this cohort of patients. DPP-4 inhibitors provide a physiological enhancement of incretin activity, are well tolerated and have a pronounced hypoglycemic effect. The main positive properties of DPP-4 inhibitors include a low incidence of hypoglycemia and a neutral effect on body weight, which is of particular importance in the treatment of elderly patients with T2DM. High clinical efficacy of vildagliptin therapy has been demonstrated in the population of patients with T2DM over 75 years of age.
Information about the author: Mikhail Borisovich Antsiferov – Doctor of Medical Sciences, Professor, Chief Physician of the Endocrinological Dispensary of the Moscow Department of Health. Email
