Received Metformin Monotherapy Research Articles

Effect of metformin therapy on the development of vitamin B12 deficiency in patients with type 2 diabetes mellitus

Introduction. For the past decades, metformin has been the drug of choice for the treatment of patients with type 2 diabetes mellitus (T2DM). However, its long-term use leads to a number of side effects, such as the development of vitamin B12 deficiency (VB12).Aim. Assess the safety of metformin use in real clinical practice in the treatment of patients with type 2 diabetes based on the analysis of the incidence of VB12 deficiency.Materials and methods. Sixty patients with T2DM aged 27 to 65 years were examined in a city polyclinic. The average anamnestic duration of T2DM was 68 [4; 291] months. All patients were on selected hypoglycemic therapy: 19 patients (31.7%) received metformin monotherapy, and 41 patients (68.3%) received metformin as part of combination therapy. The average duration of metformin therapy was 62 [3; 291] months. All patients underwent analysis of the VB12 content in the blood serum depending on the duration of metformin intake. Results. The average VB12 level in the examined patients was 345 [99; 770] pg/ml. Normal VB12 levels were observed in 51 (85%) patients (386 [221; 770] pg/ml), VB12 deficiency (<200 pg/ml) was detected in 9 (15%) patients (146 [99; 195] pg/ml), the differences between VB12 levels were significant (p < 0.05). At the same time, in 37 (61.7%) patients with normal VB12 levels, its values were assessed as borderline (in the range of 200–450 pg/ml), and amounted to 335 [221; 470] pg/ml. VB12 deficiency developed more often in patients taking metformin for more than 1 year (16.7%), borderline VB12 levels were more often found in patients taking metformin for less than a year (58.3%) and more than 5 years (71%). However, the dependence of VB12 levels on the duration of metformin intake was not significant (p > 0.05).Conclusion. Metformin use results in the development of VB12 deficiency in every sixth patient with T2DM, primarily after one year of treatment.

Glucose metabolism disorders and hypoglycemic therapy in patients hospitalized for elective lower limb arthroplasty: a prospective, single-center, real-world study

To assess the incidence of glucose metabolism disorders, administered hypoglycemic therapy and its effectiveness in a cohort of patients with previously diagnosed diabetes mellitus (DM) hospitalized for scheduled lower limb joint arthroplasty. The study included 502 patients. Medical history, information about previously diagnosed DM and prescribed hypoglycemic therapy were collected in all patients according to medical documentation, as well as according to the patients' survey. Within the preoperative examination, the glucose level was measured, and in patients with previously diagnosed diabetes, measuremaent of the HbA1c level was recommended. The study population included 180 (35.9%) males and 322 females (64.1%). Among them, 99 (19.7%) patients had disorders of glucose metabolism [type 1 diabetes - 1 (0.2%) patient, type 2 diabetes - 90 (17.9%) patients, impaired glucose tolerance (IGT) - 8 (1.6%) patients]. In 8 patients, type 2 diabetes was newly diagnosed during the preoperative examination. HbA1c was measured before hospitalization in 26 patients with diabetes, the mean level was 7.0±1.4%. Regarding the analysis of hypoglycemic therapy, almost half of the patients with DM - 47 (47.5%) - received metformin monotherapy, 8 patients with IGT and 8 patients with newly diagnosed DM did not receive any drug therapy. Target glycemic levels during therapy were achieved in 36 (36.4%) patients, and target HbA1c levels were achieved in 21 patients. The cohort of patients hospitalized for elective lower limb joint arthroplasty is characterized by a relatively high incidence of glucose metabolism disorders, and in some patients, DM was newly diagnosed during the preoperative examination. Metformin is most often used as hypoglycemic therapy, and the target values of glycemia during treatment were achieved in less than half of the patients. The monitoring of the level of glycated hemoglobin is low and requires additional population analysis in order to determine the causes and optimize the strategy of patient management.

Metformin Use in the First Trimester of Pregnancy and Risk for Nonlive Birth and Congenital Malformations: Emulating a Target Trial Using Real-World Data.

Metformin is a first-line pharmacotherapy for type 2 diabetes, but there is limited evidence about its safety in early pregnancy. To evaluate the teratogenicity of metformin use in the first trimester of pregnancy. In an observational cohort of pregnant women with pregestational type 2 diabetes receiving metformin monotherapy before the last menstrual period (LMP), a target trial with 2 treatment strategies was emulated: insulin monotherapy (discontinue metformin treatment and initiate insulin within 90 days of LMP) or insulin plus metformin (continue metformin and initiate insulin within 90 days of LMP). U.S. Medicaid health care administration database (2000 to 2018). 12 489 pregnant women who met the eligibility criteria. The risk and risk ratio of nonlive births, live births with congenital malformations, and congenital malformations among live births were estimated using standardization to adjust for covariates. A total of 850 women were in the insulin monotherapy group and 1557 in the insulin plus metformin group. The estimated risk for nonlive birth was 32.7% under insulin monotherapy (reference) and 34.3% under insulin plus metformin (risk ratio, 1.02 [95% CI, 1.01 to 1.04]). The estimated risk for live birth with congenital malformations was 8.0% (CI, 5.7% to 10.2%) under insulin monotherapy and 5.7% (CI, 4.5% to 7.3%) under insulin plus metformin (risk ratio, 0.72 [CI, 0.51 to 1.09]). Possible residual confounding by glycemic control and body mass index. Compared with switching to insulin monotherapy, continuing metformin and adding insulin in early pregnancy resulted in little to no increased risk for nonlive birth among women receiving metformin before pregnancy. Under conventional statistical criteria, anything between a 49% decrease and a 9% increase in risk for congenital malformations was highly compatible with our data. National Institutes of Health.

Sodium-Glucose Cotransporter-2 Inhibitors vs Sulfonylureas for Gout Prevention Among Patients With Type 2 Diabetes Receiving Metformin

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are a revolutionary treatment for type 2 diabetes (T2D) with cardiovascular, kidney, and serum urate-lowering benefits. To compare risk of incident gout and rate of recurrent flares between patients with T2D initiating SGLT2i vs sulfonylurea, most common second-line glucose-lowering therapy, when added to metformin monotherapy. This sequential, propensity score-matched, new-user comparative effectiveness study using target trial emulation framework included adults with T2D receiving metformin monotherapy in a Canadian general population database from January 1, 2014, to June 30, 2022. Initiation of SGLT2i vs sulfonylurea. The primary outcome was incident gout diagnosis, ascertained by emergency department (ED), hospital, outpatient, and medication dispensing records. Secondary outcomes were gout-primary hospitalizations and ED visits and major adverse cardiovascular events (MACE), as well as recurrent flare rates among prevalent gout patients. Heart failure (HF) hospitalization was assessed as positive control outcome and osteoarthritis encounters as negative control. For target trial emulations, we used Cox proportional hazards and Poisson regressions with 1:1 propensity score matching (primary analysis) and overlap weighting (sensitivity analysis). The analysis was conducted from September to December, 2023. Among 34 604 propensity score matched adults with T2D initiating SGLT2i or sulfonylurea (20 816 [60%] male, mean [SD] age, 60 [12.4] years), incidence of gout was lower among SGLT2i initiators (4.27 events per 1000 person-years) than sulfonylurea initiators (6.91 events per 1000 person-years), with a hazard ratio (HR) of 0.62 (95% CI, 0.48-0.80) and a rate difference (RD) of -2.64 (95% CI, -3.99 to -1.29) per 1000 person-years. Associations persisted regardless of sex, age, or baseline diuretic use. SGLT2i use was also associated with fewer recurrent flares among gout patients (rate ratio, 0.67; 95% CI, 0.55-0.82; and RD, -20.9; 95% CI, -31.9 to -10.0 per 1000 person-years). HR and RD for MACE associated with SGLT2i use were 0.87 (95% CI, 0.77-0.98) and -3.58 (95% CI, -6.19 to -0.96) per 1000 person-years. For control outcomes, SGLT2i users had lower risk of HF (HR, 0.53; 95% CI, 0.38-0.76), as expected, with no difference in osteoarthritis (HR, 1.11; 95% CI, 0.94-1.34). Results were similar when applying propensity score overlap weighting. In this population-based cohort study, the gout and cardiovascular benefits associated with SGLT2i in these target trial emulations may guide selection of glucose-lowering therapy in patients with T2D, at risk for or already with gout.

Evaluating the Efficacy, Safety, and Tolerability of Combination Therapy of Dapagliflozin and Linagliptin Over Dapagliflozin and Vildagliptin in Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin.

Background Type 2 diabetes mellitus (T2DM) patients commonly undergometformin monotherapy.This study aims to compare the efficacy, safety, and tolerability of combination therapy of dapagliflozin plus linagliptin versus dapagliflozin plus vildagliptin as add-on therapy in T2DM patients inadequately controlled on metformin. Methodology This was an 18-week, multicenter, randomized, double-blind, active-controlled, parallel-group, phase III clinical study. About 236 participants were randomly assigned to receive either a fixed-dose combination of dapagliflozin 10 mg plus linagliptin 5 mg tablets or a fixed-dose combination of dapagliflozin 10 mg plus vildagliptin SR 100 mg tablets added to metformin monotherapy. The primary outcome was the mean change in hemoglobin A1c (HbA1c) from baseline to the end of week 16. The key secondary endpoints were mean change in postprandial blood glucose (PPBG), fasting blood glucose (FBG), body weight, and the proportion of participants achieving HbA1c less than 7.0%. Results The dapagliflozin/linagliptin combination therapy showed a more significant change in HbA1c from baseline to the end of 16 weeks (mean reduction: -1.59% vs. -1.25%) compared to dapagliflozin/vildagliptin (p < 0.0001). Additionally, compared to the dapagliflozin/vildagliptin group, the dapagliflozin/linagliptin group demonstrated a significant reduction in both PPBG (mean reduction: -59.99 mg/dL vs. -55.34 mg/dL) and FPG (mean reduction: -32.91 mg/dL vs. -26.78 mg/dL). A total of 18 adverse events were reported in 17 (7.20%) participants, all of which were mild and resolved completely. There were no serious adverse events. Conclusions Compared to dapagliflozin and vildagliptin combination therapy, dapagliflozin and linagliptin fixed-dose combination provided clinically significant improvements in glycemic control. Because of its effectiveness, safety, and tolerability, the fixed-dose combination of dapagliflozin and linagliptin was a better option for treating T2DM patients who had previously only received metformin monotherapy.

Effectiveness and Safety of Sodium-Glucose Cotransporter2 Inhibitors Added to Dual or Triple Treatment in Patients with Type2 Diabetes Mellitus.

We evaluated the effectiveness and safety of sodium-glucose cotransporter2 inhibitor (SGLT2i) add-on treatment in patients with type2 diabetes mellitus (T2DM) in the real-world setting. This single-center retrospective study used the clinical database of Seoul National University Hospital in South Korea. Patients who received metformin monotherapy or combination therapy with ≥ 1 other oral hypoglycemic medication and had a baseline glycosylated hemoglobin (HbA1c) between 7.0% and 10.5% were included. Propensity score matching was applied between patients treated with and without SGLT2 inhibitors (SGLT2i and non-SGLT2i groups, respectively). Changes in HbA1c from baseline to week26 were compared between the SGLT2i and non-SGLT2i groups, and risk of adverse events (AE) were also assessed. A total of 1106 patients were included. At week26, HbA1c was significantly more reduced by 0.35 percentage points in the SGLT2i group than in the non-SGLT2i group (95%CI 0.30-0.41, P < 0.001). Likewise, the proportion of patients achieving HbA1c < 7% was also significantly higher (51.9% vs. 37.6%, P < 0.05) in the SGLT2i group than in the non-SGLT2i group. The risk of adverse events in the SGLT2i group was mostly comparable with those in the non-SGLT2i group except for diseases of the liver, pain, hypertensive diseases, and metabolic disorders, which showed significantly higher odds in the SGLT2i group. SGLT2i add-on treatment is an effective and safe therapeutic option for patients with T2DM in the real-world practice setting.

Multinational patterns of second line antihyperglycaemic drug initiation across cardiovascular risk groups: federated pharmacoepidemiological evaluation in LEGEND-T2DM

ObjectiveTo assess the uptake of second line antihyperglycaemic drugs among patients with type 2 diabetes mellitus who are receiving metformin.DesignFederated pharmacoepidemiological evaluation in LEGEND-T2DM.Setting10 US and seven non-US electronic health...

Association of Met420del Variant of Metformin Transporter Gene SLC22A1 with Metformin Treatment Response in Ethiopian Patients with Type 2 Diabetes.

This study aimed to evaluate whether the M420del variants of SLC22A1 (rs72552763) is associated with metformin treatment response in Ethiopian patients with type 2 diabetes mellitus (T2DM). A prospective observational cohort study was conducted on 86 patients with T2DM who had been receiving metformin monotherapy for <1 year. Patients showing ≥0.5% reduction in HbA1c levels from baseline within 3 months and remained low for at least another 3 months were defined as responders while those patients with <0.5% reduction in HbA1c levels and/or those whom started a new class of glucose-lowering drug(s) because of unsatisfactory reduction were defined as non-responders. In addition, good glycemic control was observed when HbA1c ≤7.0%, and the above values were regarded as poor. Genotyping of rs72552763 SNP was performed using TaqMan® Drug Metabolism Enzyme Genotyping Assay and its association with metformin response and glycemic control were assessed by measuring the change in HbA1c and fasting blood glucose levels using Chi-square, logistic regression and Mann-Whitney U-test. Statistical significance was set at p <0.05. The minor allele frequency of the rs72552763 SNP of SLC22A1 was 9.3%. Metformin response was significantly higher in deletion_GAT (del_G) genotypes as compared to the wild-type GAT_GAT (G_G) genotypes. Furthermore, a significantly lower median treatment HbA1 level was found in del_G genotypes as compared to G_G genotypes. However, the association of rs72552763 with metformin response was not replicated at the allele level. In contrast, the minor del_allele was significantly associated with good glycemic control compared to the G_allele, though not replicated at del_G genotypes level. This study demonstrated that metformin response was significantly higher in study participants with a heterozygous carrier of M420del variants of SLC22A1 as compared to the wild-type G_G genotypes after 3 months of treatment.

Pathology of carbohydrate metabolism in primary hyperparathyroidism: epidemiological and clinical characteristics

Primary hyperparathyroidism (PHPT) is characterized by disorders of not only mineral metabolism, but also other kinds of the human metabolism. Due to the increased frequency of cardiovascular risk factors among patients with PHPT, the study of the carbohydrate metabolism pathology in this cohort of patients will allow developing optimal approaches to their timely diagnosis and treatment.Aim. To determine the frequency and describe the clinical features of carbohydrate metabolism disorders in patients with PHPT.Material and methods. A single-center retrospective study of adults with PHPT was carried out with an assessment of the main parameters of mineral and carbohydrate metabolism before surgical treatment of the disease. The exclusion criteria were the absence of PHPT remission or a recurrence of the disease after parathyroidectomy; pregnancy, lactation. The frequency of various disorders of carbohydrate metabolism in PHPT, the comparative characteristics of mineral parameters in patients with and without them, as well as the severity of type 2 diabetes mellitus in PHPT were determined. In addition, potential relationships between the parameters of various types of metabolism have been studied.Results. The study was based on a clinical information of 367 patients with PHPT, most of whom had a symptomatic form of the disease. The overall incidence of prediabetic disorders was 4,9% (95% CI: 3-8). Type 2 diabetes mellitus was previously diagnosed in 45 patients (12%, 95% CI: 9-16), there were no cases of first diagnosed diabetes mellitus. Individuals with impaired carbohydrate metabolism had a statistically significantly higher body mass index and lower values of osteocalcin (27,2 [24,2; 30,4] kg/m2 vs 32,7 [28,1; 39,4 kg/m2 and 48,1 [34; 76,3] ng/mL vs 33,1 [20,8; 51,8] ng/mL, respectively, for all parameters p&lt;0,001). Among patients with type 2 diabetes mellitus, 36 people (80%) took hypoglycemic therapy, 14 of which received metformin monotherapy and 8 received two-component therapy, including metformin. 5 people were on insulin therapy. Diabetic nephropathy was diagnosed in 36,4% of patients, 15,4% had signs of diabetic retinopathy, symptoms of diabetic distal neuropathy were observed in 61,9% of patients with PHPT. Fasting glucose and glycated hemoglobin were negatively correlated with bone metabolism, and also expectedly depended on the glomerular filtration rate.Conclusion. Among patients with PHPT, type 2 diabetes mellitus is more common than in the general population. The likely reason of this may be insulin resistance, that can be caused by the effects of bone metabolites, primarily osteocalcin. In most cases, metformin makes it possible to achieve compensation for diabetes mellitus in PHPT.

Impact of Race and Ethnicity on Severe Hypoglycemia Associated with Sulfonylurea Use for Type 2 Diabetes among Veterans.

Sulfonylureas are associated with hypoglycemia. Whether a racial/ethnic disparity in this safety outcome exists is unknown. We sought to assess the impact of race/ethnicity on severe hypoglycemia associated with sulfonylurea use for type 2 diabetes (T2D). Using Veterans Affairs and Medicare data, Veterans initially receiving metformin monotherapy for T2D between 2004 and 2006 were identified. Sulfonylurea use (either alone or via the addition of a prescription for a sulfonylurea to metformin) was captured and compared to remaining on metformin alone during the follow-up period (2007-2016). Hazard ratios (HR) and 95% confidence intervals (CI) from longitudinal competing risk Cox models were used to measure the association between sulfonylurea use and severe hypoglycemia defined as hospitalization for hypoglycemia. A total of 113,668 Veterans with T2D were included. A higher risk of severe hypoglycemia was associated with the receipt of sulfonylurea prescriptions versus remaining on metformin alone across all groups. The effect was largest among Hispanic Veterans (HR: 7.59, 95%CI:4.32-13.33), followed by Veterans in the other race/ethnicity cohort (HR: 4.57, 95%CI:2.50-8.36) and Non-Hispanic Black Veterans (HR: 3.67, 95%CI:2.78-4.85). The effect was smallest among Non-Hispanic White Veterans (HR: 3.11, 95%CI:2.77-3.48). In conclusion, a higher risk of severe hypoglycemia associated with sulfonylurea prescriptions was observed across all analyses. The relationship was most pronounced for Hispanic Veterans, who had nearly 8 times the risk of severe hypoglycemia with sulfonylureas versus remaining on metformin alone.

Sulfonylureas as second line therapy for type 2 diabetes among veterans: Results from a National Longitudinal Cohort Study

AimsTo assess if switching to or adding sulfonylureas increases major adverse cardiovascular events (MACE) or severe hypoglycemia versus remaining on metformin alone. Materials and MethodsThis was a retrospective, longitudinal cohort utilizing United States Veterans Health Administration and Medicare data. Veterans with type 2 diabetes on metformin monotherapy between 2004 and 2006 were identified. Follow-up occurred through 2016. Those treated with either metformin plus a second-generation sulfonylurea (N = 45,305) or converted from metformin to a second-generation sulfonylurea (N = 2813) were compared to those receiving metformin monotherapy (N = 65,550). Hazard ratios (HR) and 95%CI from longitudinal competing risk Cox models were used to measure the association between sulfonylureas and outcomes. ResultsSwitching to or adding a sulfonylurea to metformin was associated with 3 times the risk of severe hypoglycemia versus metformin monotherapy (HR:3.44, 95% CI: 3.06,3.85 and HR: 3.08, 95% CI: 2.77,3.42, respectively). Switching to or adding a sulfonylurea to metformin was associated with a 7–19% higher risk of MACE versus metformin monotherapy (HR: 1.07, 95% CI: 1.00,1.14 and HR: 1.19, 95% CI: 1.13,1.25, respectively). ConclusionsSwitching to and adding second-generation sulfonylureas was associated an increase in severe hypoglycemia and MACE versus remaining on metformin alone. In an era where guidelines recommend diabetes therapies based on compelling indications, safety outcomes should be a key consideration when selecting therapy.

Treatment pattern trends of medications for type 2 diabetes in British Columbia, Canada

IntroductionSeveral new oral drug classes for type 2 diabetes (T2DM) have been introduced in the last 20 years accompanied by developments in clinical evidence and guidelines. The uptake of new...

125-LB: Individualized Cost-Effectiveness Assessment of Sodium–Glucose Cotransporter 2 Inhibitors (SGLT2i) vs. Sulfonylureas as Add-On Therapy in People with Inadequately Controlled Type 2 Diabetes (T2D) Under Metformin Monotherapy

The cost-effectiveness of SGLT2i can be modulated by patients’ characteristics, such as cardiovascular risks. We performed an individualized cost-effectiveness assessment of SGLT2i when added to metformin in people with inadequately controlled T2D to quantify the modulating effect of patients’ characteristics on the cost-effectiveness of SGLT2i. We identified survey participants with T2D receiving metformin monotherapy who had an A1c level above 7.0% from the National Health and Nutrition Examination Survey (2013-2018) . We applied a simulation-based smoothing method to populate the survey sample to its represented national population. We used the BRAVO diabetes model to simulate the lifetime cost and QALYs associated with SGLT2i or sulfonylureas. Treatment escalations were governed by the A1c level at 7% and 8% consequentially. Both costs and QALYs were discounted at 3% annually, and the incremental cost-effectiveness ratio (ICER) threshold was set at $100,000/QALYs. The study sample included 2.89 million individuals. Compared with sulfonylureas, the use of SGLT2i was associated with an average of $9,400 higher medical cost and 0.10 additional QALY, leading to an ICER of $94,000/QALY in the overall population. SGLT2i was cost-effective in people with a history of heart failure (ICER: $67,000/QALY) and myocardial infarction (ICER: $94,000/QALY) , and marginally cost-effective in stroke patients (ICER: $100,000/QALY) . Among individuals without CVD, SGLT2i was cost-effective only in subgroups with HbA1c &amp;gt; 7.5%, age &amp;gt; 60, and diabetes duration &amp;gt; 10 years. Overall, SGLT2i was only cost-effective in individuals with a baseline 10-year CVD risk over 16%, constituting 51.6% of the overall population. Our results align closely with the ADA guideline on the recommended population for SGLT2i use. Out-of-pocket payment subsidy or cost-sharing reduction of SGLT2i should be prioritized in patient subgroups in which SGLT2i has high economic values. Disclosure D. Guan: None. S. Niu: None. V. Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. L. Shi: None. N. Laiteerapong: None. J. Guo: None. H. Shao: Board Member; BRAVO4HEALTH, LLC.

Association of the SLC47A1 Gene Variant With Responses to Metformin Monotherapy in Drug-naive Patients With Type 2 Diabetes

Although metformin is the first-line treatment for type 2 diabetes, the blood sugar-lowering effect of metformin varies among populations. SLC47A1 plays an important role in metformin pharmacokinetics and pharmacodynamics. We performed a systematic review and meta-analysis to investigate the association between SLC47A1 rs2289669 (G > A) and the metformin response in drug-naive patients with type 2 diabetes. Studies published until January 27, 2022, were retrieved from Cochrane CENTRAL, Embase, PubMed, and Web of Science. Two reviewers independently screened titles, abstracts, and full-text articles. Studies conducted in newly diagnosed or drug-naive patients with type 2 diabetes who received metformin monotherapy were included. A total of 6 studies involving 953 patients were included in this meta-analysis. We extracted the study characteristics and changes in glycated hemoglobin (HbA1c) levels before and after treatment according to the SLC47A1 rs2289669 genotype. Changes in HbA1c levels were analyzed using mean differences (MDs) and 95% CIs. SLC47A1 rs2289669 was associated with changes in HbA1c levels (A carrier vs GG; MD = -0.55; 95% CI, -0.91 to - 0.20; I² = 63%). The sensitivity analysis yielded similar results to the main analysis (MD range, -0.64 to -0.37). When comparing all 3 genotypes, there were significant differences in HbA1c level changes between AA vs GG and GA vs GG, but not in GA vs AA. This meta-analysis showed that SLC47A1 rs2289669 is associated with the glycemic response to metformin in drug-naive patients with type 2 diabetes.

The influence of SLC22A3 rs543159 and rs1317652 genetic variants on metformin therapeutic efficacy in newly diagnosed patients with type 2 diabetes mellitus: 25 weeks follow-up study

Background and aimsAmong anti-diabetic medications, metformin has been proven to be the preferred initial pharmacologic agent for type 2 diabetes mellitus (T2DM) treatment. Despite its safety and efficacy, the response to metformin varies between individuals. Genetic variations, especially within genes involved in pharmacokinetics and pharmacodynamics of metformin (e.g SLC22A3), have been suggested to be responsible for the observed inter-individual differences. By considering the undeniable role of organic cation transporter 3 in hepatic uptake of metformin, this study was aimed to investigate the association of rs543159 and rs1317652 variants in SLC22A3 gene with response to metformin monotherapy in newly diagnosed patients with T2DM. MethodsThe study included 200 T2DM patients who received metformin monotherapy for 25 weeks. The patients were classified into 2 groups according to their HbA1c values: the responders (reduction in HbA1c levels by at least 1% after 25 weeks treatment with metformin) and non-responders (less than 1% reduction in HbA1c levels after 25 weeks treatment with metformin). We used tetra ARMS-PCR method to determine genotypes of the target variants. ResultsFor the rs543159, CA and AA genotypes were more frequent in responders as compared to non-responders (OR = 2.48; 95% CI = 1.28–4.78, P-value = 0.0057) under the dominant model. In case of rs1317652 CC and CT genotypes were more frequent in metformin responders as compared to non-responder group (OR = 2.49; 95% CI = 1.32–4.70, P-value = 0.0043) under the dominant model. Parameters such as fasting blood sugar (FBS), HbA1c, and total cholesterol (TC) levels were significantly lower in the responder group after 25 weeks of metformin monotherapy. Moreover, according to the result of multiple linear regression rs543159 and base line HbA1c values are significantly associated with response to metformin monotherapy. ConclusionOur results suggested that rs543159 and rs1317652 in SLC22A3 gene might be associated with variability in response to metformin therapy in T2DM patients.

Evaluation of the Vasoprotective Effects of Metformin versus Glibenclamide in Type 2 Diabetic Patients

Adiponectin (APN) is an adipokine with anti-inflammatory and anti-atherogenic properties decreased in type 2 diabetes mellitus (T2DM) that may influence endothelial function by regulating serum nitric oxide (NO) levels. The current study aimed to investigate the effect of two oral hypoglycemic drugs, Metformin and Glibenclamide (GLC), on circulating APN and NO levels and to find a correlation between APN and NO levels in type 2 diabetic patients. Fifty males and females previously diagnosed with T2DM were conducted in this trial and classified into groups: Group A involved 18 untreated patients with T2DM, group B involved 16 patients receiving Metformin monotherapy (1000 mg/day) for up to 1 year and group C involved 16 patients receiving GLC (5 mg/day) for up to 1 year. Circulating APN and NO were measured. Compared to GLC, Metformin therapy showed a significant increase in APN and NO levels in type 2 diabetic patients. Our findings established that Metformin has a protective effect on endothelial function, including increased APN and NO bioavailability, beyond its glucose-lowering effect.

Type 2 diabetes mellitus in children and adolescents in the world and in Ukraine

Introduction. Recently, many studies have been devoted to the study of type 2 diabetes mellitus (DM2) worldwide. In most countries of the world, the increase in the prevalence of DM2 among children and adolescents is accompanied by an increase in childhood obesity. The presence of obesity or overweight in children can complicate the diagnosis of various types of DM. Detection and treatment of DM2 is extremely important for the society due to the wide range of severe diabetes complications.The aim of this work was to analyze the frequency of DM2 according to the Register of patients with DM, and to determine the state of glycemic control in children with DM2. Materials and methods. An analysis of glycemic control in children with DM2 who received various treatment regimens: with diet and lifestyle modifications, or with additional oral hypoglycemic agents (metformin monotherapy, or combination with insulin therapy). The glycemic control was assessed by measurement of glycated hemoglobin (HbA1c) level. Results. According to the data Register in Ukraine, the prevalence of DM among children has a tendency to rise — from 8.6 per 10 thousand children in 2005, to 13.14 — in 2019 year. The prevalence of DM2 in 2019 was 0.47 % of all cases of DM, and its prevalence contained 0.062 per 10 thousand children under 19 years of age with significant differences in the frequency of its diagnosis in different regions of Ukraine. We analyzed the state of glycemic control in children with DM2 aged from 9 up to 19 years old (Me 16.2 [15.5; 18.0]), with a disease duration 0.5—12 years (Me 4.5 [1.0] ; 7.5]). The age of diagnosis of DM2 was 2-17 years old (Me 11.7 [8.5; 15.0]), and 91.3 % of patients had obesity. Diet and lifestyle modifications were used in 34.8 % of patients, metformin monotherapy in 52.2 %, and metformin and insulin combination therapy in 13 % of patients. HbA1c values ​​ranged from 5.0 to 11.4 % (Me 7.2 % [5,8; 8,0]). The proportion of children who had ideal or optimal glycemic control (HbA1c 7.0—7.5 %) was 52.2 %, suboptimal (HbA1c 7.6—9.0 %) — 39.1 %, high-risk glycemic control (HbA1c&gt; 9.1 %) — 8.7 % of children. The most unsatisfactory HbA1c levels ​​were registered in children who received metformin in combination with insulin (Me 10.6 % [10,15; 11,4]). Chronic complications of DM2 have not been reported.Conclusions. We found a low prevalence of DM2 among the pediatric population in Ukraine, more likely due to the low quality of its detection among children diagnosed with DM, as well as among children among high risk groups. Most children with DM 2 were obese. The majority of patients with DM2 (52.2 %) received metformin monotherapy, more than a third did not receive oral hypoglycemic agents. In most children with DM2 (52,2 %), the state of glycemic control corresponded to the optimal (&lt; 7.5 %), but higher levels of HbA1c were found children who received metformin in combination with insulin.

Ефективність і патогенетичне обґрунтування застосування вілдагліптину у хворих на цукровий діабет 2-го типу

Актуальність. Інгібітори дипептидилпептидази 4-го типу (ДПП-4), маючи інкретинову активність, впливають на основні патогенетичні механізми цукрового діабету (ЦД) 2-го типу. Вілдагліптин є інноваційним препаратом класу інгібіторів ДПП-4 з унікальними характеристиками фармакокінетики, ефективність і безпека якого вивчалися в плацебо-контрольованих дослідженнях. Мета дослідження: вивчення фармакотерапевтичної ефективності, безпеки й переносимості препарату Гліптар виробництва ПАТ «Київмедпрепарат» (Україна) у терапії хворих на ЦД 2-го типу. Матеріали та методи. У дослідження було включено 49 пацієнтів із ЦД 2-го типу. До включення в дослідження хворі отримували монотерапію метформіном у дозі не менше за 1000 мг на добу принаймні упродовж останніх шести місяців. Тривалість перебігу ЦД 2-го типу в середньому становила 6,2 ± 1,8 року. Пацієнти сформували дві групи для подальшого спостереження. 29 пацієнтам, які до цього часу отримували препарати метформіну в дозі до 2000 мг/добу, був додатково призначений препарат Гліптар (вілдагліптин) у дозі 50 мг двічі на добу. Пацієнти другої групи (n = 20) продовжували прийом метформіну двічі на день в дозі 2000 мг/добу. Результати. Через 12 тижнів у хворих першої групи на тлі терапії метформіном у поєднанні з вілдагліптином рівень НbА1с вірогідно знизився до 6,42 ± 0,21 %, глікемія натще — до 6,14 ± 0,22 ммоль/л, глікемія постпрандіальна — до 8,63 ± 0,23 ммоль/л. На тлі комбінованого лікування у хворих на ЦД 2-го типу відзначалися зниження маси тіла на 1,18 кг, а також тенденція до зниження індексу маси тіла з 31,49 ± 1,08 кг/м2 до 29,98 ± 0,76 кг/м2. Рівень імунореактивного інсуліну становив після лікування в першій групі 14,08 ± 1,83 мкОд/мл (при початковому 21,11 ± 2,03 мкОд/мл), індекс HOMA-IR — 3,14 ± 0,21 (проти початкового 6,28 ± 1,42). Вірогідне зниження показників вуглеводного обміну, інсулінорезистентності можна оцінювати як позитивну динаміку завдяки комбінованому лікуванню. Висновки. З огляду на отримані переваги подвійної терапії в лікуванні хворих на ЦД 2-го типу відповідно до загальноприйнятої покрокової терапії на другому етапі пацієнтам, які отримують метформін і не досягли цільового глікемічного контролю, доцільно призначати препарат вілдагліптину. Комбінована терапія вілдагліптином у поєднанні з метформіном забезпечує комплексну дію на чинники ризику серцево-судинних захворювань у вигляді запобігання розвитку гіперінсулінемії та зниження інсулінорезистентності.

Comparative effects of metformin and glibenclamide on the redox balance in type 2 diabetic patients

It is known that there is a strong association between oxidative stress and insulin resistance in type 2 diabetes mellitus (T2DM). Although the role of glibenclamide in diabetes treatment has been evaluated, there is only limited evidence about its antioxidant effects in diabetic patients. Moreover, previous studies showed discrepant results regarding the effects of metformin on antioxidant/ oxidant parameters in type 2 diabetic patients. The present study aimed to evaluate the effects of metformin versus glibenclamide on oxidative stress biomarkers, represented by serum malondialdehyde (MDA), nonenzymatic, and enzymatic antioxidants in type 2 diabetic patients. Forty-six patients with T2DM participated in this study and categorized into 3 groups, Group A included 17 newly diagnosed diabetic patients, group B included 15 diabetic patients received metformin monotherapy (1000 mg/day) for up to 1 year and group C included 14 diabetic patients received glibenclamide monotherapy (5 mg/day) for up to 1 year. Serum MDA, catalase (CAT), vitamin C, E, and reduced glutathione (GSH) were measured. We found significantly lower concentrations of MDA and significantly higher antioxidant levels (CAT, GSH, vitamin C, and E) in the metformin-treated group compared to the glibenclamide counterpart. Our data confirmed that metformin has a more beneficial effect on oxidant/antioxidant status compared to glibenclamide, therefore, provides protection against reactive oxygen species (ROS) induced oxidative damage during diabetes.

A Retrospective Study on the Effect of the Co-Administration of Ojeok-san and Hypoglycemic Agents on Blood Glucose Levels in Type 2 Diabetes Mellitus

Objective This study was conducted to investigate the hypoglycemic effect and safety of Ojeok-san in patients with type 2 Diabetes Mellitus. Methods We investigated type 2 diabetes mellitus patients at Kyung-Hee University Korean Medical Hospital who were administered Ojeok-san for at least one day between January 2012 and September 2020, basal characteristics and laboratory tests were reviewed retrospectively. The hypoglycemic effect of Ojeok-san was assessed by comparing fasting blood sugar (FBS) and two hours post-prandial plasma glucose (PP2) levels from before and after taking Ojeok-san. Subgroup analyses were conducted according to baseline hypoglycemic treatments and glycated hemoglobin levels (< or ≥6.5%). The safety of Ojeok-san was assessed by comparing levels of aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, blood urea nitrogen, and creatinine. Results After Ojeok-san administration, FBS and PP2 were significantly reduced to an average of 14.33 mg/dL and 27.67 mg/dL respectively. In the subgroup analysis, PP2 in patients receiving metformin mono therapy was significantly reduced to 28.67 mg/dL, and those receiving a dual therapy of metformin and DPP-4 inhibitor, it was significantly reduced to 32.33 mg/dL. In patients with glycated hemoglobin of lower than 6.5%, FBS was significantly reduced to 12.20 mg/dL, and both FBS and PP2 were significantly reduced, to 15.50 mg/dL and 40.00 mg/dL, respectively, in those with glycated hemoglobin levels of more than 6.5%. The safety profile showed no significant difference after Ojeok-san administration. Conclusions Ojeok-san has significant hypoglycemic effects in patients with type 2 diabetes mellitus who are also taking hypoglycemic agents. Keywords: Ojeok-san, type 2 diabetes mellitus, blood glucose level