Efficacy and safety of oral semaglutide in Russian patients with type 2 diabetes: subgroup analysis of PIONEER 1, 2, 3 trials

INTRODUCTION. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are the treatment options with comprehensive action on different aspects of type 2 diabetes. Due to its peptide nature GLP-1 RAs, until recent time the delivery of these agents into patients’ organism was via injectable devices. In 2019, the first time in history oral semaglutide was registered based on the results of PIONEER clinical trial program, since 2021 this drug is available in Russia. However, the pathophysiology of type 2 diabetes and local treatment approaches may differ in different populations; this can lead to the differences in the efficacy and safety of newly registered drug. Therefore, it is necessary to evaluate the response in different populations. In this paper we report the result of subanalysis of efficacy and safety of oral semaglutide in Russian patients.OBJECTIVE. The aim of this analysis is to evaluate efficacy and safety of oral semaglutide in Russian patients, who participated in semaglutide clinical development program, as well as to evaluate consistency and applicability of the results obtained from global population in that program.MATERIALS AND METHODS. Patients from PIONEER 1, 2, 3 were included in the analysis: 150 patients from Russian, 1956 — the rest patients from these trials. Reductions in HbA1c and body weight were analyzed in both cohorts, and treatment differences were tested for interaction. Similarly, the rate of adverse events was analyzed.RESULTS. Reduction in HbA1c in oral semaglutide arms in both cohorts showed numerically similar and consistent result. Interaction test showed statistical difference in PIONEER 1 data (p=0.0268) — the effect was due to diminishing influence of substantial response in placebo arm in Russian cohort. In longer-term trials (PIONEER 2 and 3) this finding was not confirmed (p=0.7459 and p=0.4906, respectively). In regard to body weight reduction there were more numerically pronounced results in Russian cohort compared to global population; although statistical significance were not reached in any of the trial (p>0.05). There was lower rate of reported adverse events in Russian patients compared to the rest cohort.CONCLUSION. This analysis showed similar efficacy and safety of oral semaglutide in Russian patients compared to global population of patients from clinical program

Oral semaglutide: the innovation in type 2 diabetes management

Oral semaglutide is the first-in-class glucagon-like peptide-1 receptor agonist available in the form of pills administered per os. PIONEER — the clinical trial program assessing the efficacy and safety of oral semaglutide — demonstrated the dose-­dependent efficacy of the drug: the reduction of up to -1,4% in terms of glucose-lowering effects and the decrease of up to 5 kg in terms of weight loss. Moreover, oral semaglutide is superior in this regard compared to empagliflozin 25 mg, liraglutide 1,8 mg and sitagliptin 100 mg according to the dedicated trials of clinical program. From the cardiovascular perspective oral semaglutide has been proven to be safe. Therapeutic concentration of semaglutide in oral form is reached under ­several conditions: taking tablets on a daily basis in a fasting state with up to half a glass of water and waiting 30 minutes before drinking, eating, or taking other drugs. Most frequent adverse events were GLP-1 associated gastrointestinal reactions (­nausea, vomiting and diarrhea), most of the events were transient and occurred generally during dose escalation

A simultaneous pancreas-kidney transplantation for type 1 diabetes mellitus after a long-term of receiving hemodialysis renal replacement therapy. Clinical сase

At the present time, a simultaneous pancreas-kidney transplantation (SPKT) is an effective method of treatment for patients on renal replacement therapy by hemodialysis program in the outcome of the terminal stage of diabetic nephropathy. This method of treatment solves several problems: it reduces the severity of intoxication syndrome, contributes to the achievement of euglycemia in most cases, which certainly allows to slow the progression of micro- and macrovascular complications of diabetes. Despite of positive effect of euglycaemia and kidney function normalization, the accumulated metabolic memory legacy of long-term uncompensated diabetes mellitus is realized, which makes a posttransplantational rehabilitation of patients difficult. A duration of hemodialysis therapy is known as a cardiovascular events risk factor, which affects the surgery result and favorable posttransplant period. More often after successful SPKT microvascular diabetic complications are stabilized, but macrovascular diabetic complications, diabetic neuroosteoarthropathy and mineral and bone disease are progressed. That’s why is necessary to perform regular examination after SPKT by a team of specialists, including nephrologist, endocrinologist, cardiologist, ophthalmologist with correction of ongoing therapy. Therefore both the preparation of  the patient for transplantation with the earliest possible placement on the waiting list and the post-transplant rehabilitation afterwards are extremely important

Renal effects of glucagon-like peptide receptor agonists in patients with type 1 diabetes mellitus

The purpose of our study is to assess the effects of glucagon-like peptide-1 receptor agonists (GLP-1R agonists) on early markers of kidney damage in patients with type 1 diabetes mellitus (DM). Materials and methods. The study included 27 patients with type 1 diabetes with normo- (n=16) and microalbuminuria (n=11) on intensive insulin injection regimen with insulin analogs. Patients were divided into two groups: 15 patients continued insulin therapy throughout the follow-up period, 12 patients were given 1.2 mg GLP-1R agonist (Liraglutide) once a day in addition to the insulin therapy for 6 months. HbA1c, lipid profile, classic markers of kidney damage (albuminuria, creatinine, glomerular filtration rate); plazma (neutrophilic gelatinase-associated lipoxalin - NGAL, molecule renal damage of type 1 - KIM-1, cystatin C, osteopontin) and urinary kidney biomarkers (nephrin, podocyne, uromodulin, NGAL, KIM-1, collagen type IV, cystatin C) were evaluated prior and in dynamics at 6 months. Kidney biomarkers levels were assessed by the enzyme-linked immunosorbent assay (ELISA). Results. We observed a significant decrease in the urinary excretion of type IV collagen, cystatin C, increased uromodulin excretion and decrease in the plasma levels of osteopontin, NGAL and cystatin C in the group of combined insulin and GLP-1R agonist therapy. Conclusions. Changes in the level of sensitive kidney biomarkers indicate a possible renoprotective effect of GLP-1R agonist therapy in patients with type 1 diabetes at an early stages of kidney damage

The structure of mineral and bone disorders in patients with сhronic kidney disease of the 5th dialysis stage, taking into account the presence or absence of a diagnosis of type 1 diabetes mellitus

BACKGROUND: In patients with end-stage CKD, receiving renal replacement therapy (RRT) with programmed hemodialysis (HD), the severity of complications is associated with metabolic disturbances: accumulation of uremic toxins, nephrogenic anemia, secondary hyperparathyroidism (SHPT), extraskeletal calcification, impaired clearance and rhythm of hormone secretion.AIM: To evaluate the main biochemical and hormonal parameters, and manifestations of mineral bone disease (MBD) in patients receiving RRT with HD, before and after hemodialysis, taking into account the presence or absence of diabetes mellitus.MATERIALS AND METHODS: We divided all patients receiving RRT with HD in two groups: #1 (n=24) — patients with DM, #2 (n=16) — patients without DM. All of them had their blood analyzed before and immediately after the HD. Data analysis was performed with the Statistica 13 (StatSoft, USA). A prognostically significant model was considered at p<0.05.RESULTS: The level of iPTH, both at baseline and after HD, was lower in group #1 (p<0.001). The level of alkaline phosphatase (AP) was significantly higher in group #2 (p=0.012). In both groups before HD, a high incidence of hypocalcemia was detected (according to albumin-corrected calcium in group #1 in 58.3%, in group #2 in 43.7% of cases, p = 0.366) and hyperphosphatemia (in 66.7% and in 43 .7% of cases, respectively, p=0.151). Hypocalcemia after HD in group #1 persisted in 14%, in group #2 — in 20% of cases (p>0.05); hyperphosphatemia in group #1 was completely leveled, in group #2 it persisted in 7% of cases (p=0.417). Prior to the HD session, group #1 had significantly higher levels of RAGE, glucagon, immunoreactive insulin (IRI), cortisol, and glucose than after the HD session (p<0.05). In group #2, after HD, the levels of glucagon, IRI and cortisol significantly decreased (p<0.05), and the level of 3-nitrotyrosine (3-HT) increased significantly (p=0.026). In group #1, fibrocalcinosis of the heart valves according to ECHO and calcification of the arteries of the lower extremities according to ultrasonic doplerography were more common than in group #2 (42% vs 25%, p<0.001 and 75% vs 37.5%, p=0.018, respectively). (χ2)). Compression fractures occurred with the same frequency in both groups (60%). A decrease in bone mineral density (BMD) to the level of osteopenia was noted more often in group #1 (50% vs 18.8%), and osteoporosis was more common in group #2 (68.8% vs 33.3%) (p<0.001, χ2).CONCLUSION: The low level of PTH in group #1 may reflect the effect of diabetes on calcium-phosphorus metabolism. Patients with DM have an increased risk of renal osteodystrophy with a low bone turnover because of a number of metabolic factors inherent in diabetes. At the same time, the dynamics of phosphorus and calcium indicators during the HD procedure were similar

Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease

Aim: present clinical guidelines, aimed at general practitioners, gastroenterologists, cardiologists, endocrinologists, comprise up-to-date methods of diagnosis and treatment of non-alcoholic fatty liver disease.Key points. Nonalcoholic fatty liver disease, the most wide-spread chronic liver disease, is characterized by accumulation of fat by more than 5 % of hepatocytes and presented by two histological forms: steatosis and nonalcoholic steatohepatitis. Clinical guidelines provide current views on pathogenesis of nonalcoholic fatty liver disease as a multisystem disease, methods of invasive and noninvasive diagnosis of steatosis and liver fibrosis, principles of nondrug treatment and pharmacotherapy of nonalcoholic fatty liver disease and associated conditions. Complications of nonalcoholic fatty liver disease include aggravation of cardiometabolic risks, development of hepatocellular cancer, progression of liver fibrosis to cirrhotic stage.Conclusion. Progression of liver disease can be avoided, cardiometabolic risks can be reduced and patients' prognosis — improved by the timely recognition of diagnosis of nonalcoholic fatty liver disease and associated comorbidities and competent multidisciplinary management of these patients

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Diabetes mellitus type 2 in adults

Public organization &ldquo;Russian Association of Endocrinologists&rdquo;. Clinical guidelines.&nbsp

Diabetes mellitus type 1 in adults

Public organization &ldquo;Russian Association of Endocrinologists&rdquo;. Clinical guidlines

Hyperphosphatemia in chronic kidney disease

Hyperphosphatemia in renal pathology is a key factor for developing mineral and bone disorders. It can develop even in the early stages of renal function decline and predict the formation of vascular calcification and an increased risk for developing cardiovascular complications in patients with chronic kidney disease, especially in those, who receive program hemodialysis. The use of calcium-free phosphate-binding agents that are not associated with the risk for developing hypercalcemia can slow the development of vascular calcification, reduce the incidence of adverse cardiovascular events and mortality in patients with chronic kidney disease