Breaking Barriers With Basal Insulin Biosimilars in Type 2 Diabetes.

Despite increases in the availability and effectiveness of other therapies, insulin remains an essential treatment for approximately 30 million people with type 2 diabetes worldwide. The development of biosimilars has created the potential for significant health care cost savings and may lead to greater access to basal insulin for vast populations. In this review, we discuss evidence demonstrating equipoise between basal insulin biosimilars and the patented analogs they may replace.

The role of GLP-1 receptor agonists and their fixed combination with insulin in the treatment of type 2 diabetes mellitus.

Therapy with GLP1 receptors agonists shows various multiorgans benefits. Possible reasons of preference of this treatment are: efficacy, decrease of weight, CV protectivity, slow down the progression of nephropathy, protection of function of B-cells, safety (low risk of hypoglycemia, small incidence of serious adverse events), decrease of blood pressure, lipids, biomarkers of CV risk, markers of chronic subclinical inflammation. In context of individual approach, therapy with GLP1 receptors agonists should be preferably used in early stages of type 2 diabetes mellitus, as second choice treatment after metformin, mainly in more obese patients with subclinical or clinical manifestations of atherosclerosis, but without symptoms of heart failure.

[A consensual therapeutic recommendation for type 2 diabetes mellitus by the Slovak Diabetes Society (2018)]. / Konsenzuálne terapeutické odporúcanie Slovenskej diabetologickej spolocnosti pre diabetes mellitus 2. typu (2018).

Type 2 diabetes mellitus is a heterogeneous medical condition involving multiple pathophysiological mechanisms. Its successful treatment requires an individualized approach and frequently combined therapy with utilizing its effect on multiple levels. Current possibilities enable the employment of such procedures to an incomparably greater extent than before. The effects of different classes of oral antidiabetic drugs on the reduction of glycemia and HbA1c is mutually comparable. However differences are observed in the proportions of patients who met the required criteria, regarding the increase in weight, incidence of hypoglycemia as well as the effect on cardiovascular, renal or oncologic morbidity and mortality, and severity of specific adverse effects, potential risks and contraindications. The presented text provides the reader with the information about the Consensual therapeutic algorithm for the treatment of type 2 diabetes mellitus in compliance with SPC, the ADA/EASD amended indicative limitations and recommendations, formulated by the Committee of the Slovak Diabetes Society.Key words: biguanides - gliflozins - gliptins - glitazones - GLP-1-receptor agonists - insulin - sulfonylurea.

A pharmacogenetic association between a variation in calpain 10 (CAPN10) gene and the response to metformin treatment in patients with type 2 diabetes.

PURPOSE: The aim of the present study was to investigate possible associations of the single-nucleotide variants in six genes encoding the key molecules mediating the metformin pharmacodynamic effect with the response to treatment with metformin in patients with type 2 diabetes. METHODS: One hundred forty-eight drug-naïve patients with type 2 diabetes were included in the study. PRKAA1 rs249429, STK11 rs741765, PCK1 rs4810083, PPARGC1A rs10213440, HNF1A rs11086926, and CAPN10 rs3792269 variants were genotyped. The outcomes of the study were treatment success defined by achieving HbA1c <7 % and absolute reduction in HbAlc after 6-month metformin therapy. The relationships between genotypes and outcomes were evaluated in multivariate logistic and linear models. The level of statistical significance after Bonferroni correction was predefined as p<0.0083. RESULTS: The minor G-allele of CAPN10 rs3792269 A>G polymorphism was significantly associated with less treatment success with an odds ratio of 0.27 (95 % CI 0.12-0.62, p=0.002) per variant allele. When the reduction in HbA1c was analyzed as a quantitative trait, G-allele was nominally associated with a smaller reduction in HbA1c (per allele ß=-0.26, 95 % CI -0.50 to -0.02, p=0.032). The reduction in HbA1c in minor allele carriers (24 % of study population) was smaller by 0.3 % in comparison with the major allele homozygotes. CONCLUSIONS: The present study provides the first observation of an association between a variant in CAPN10 gene and the response to metformin therapy in patients with type 2 diabetes. This observation needs to be replicated in further studies in different populations.

Variation in KCNQ1 is associated with therapeutic response to sulphonylureas.

BACKGROUND: We aimed to analyse quantitative effects of treatment with sulphonylurea in addition to metformin on parameters of glycemic control in relation to KCNQ1 genotypes, and to identify factors predictive for the response to sulphonylurea treatment. MATERIAL/METHODS: Effect of 6-month sulphonylurea therapy in addition to metformin on glycemic control according to KCNQ1 genotypes was evaluated in 87 patients with type 2 diabetes who failed to achieve glycemic control on metformin monotherapy. KCNQ1 rs163184 (T>G) polymorphism was determined by real-time PCR with melting analysis of unlabeled probe. RESULTS: The reduction in fasting plasma glucose (ΔFPG) after 6-month sulphonylurea therapy significantly differed among 3 KCNQ1 genotype groups (ANOVA, p=0.017). In a recessive genetic model, carriers of the T-allele (TT+TG) achieved significantly lower FPG levels in comparison with patients with the GG genotype (6.95 ± 0.13 vs. 7.50 ± 0.21 mmol/L, p=0.033). Consequently, ΔFPG was significantly higher in the TT+TG group compared to the GG group (1.58 ± 0.13 vs. 1.04 ± 0.18 mmol/L, p=0.016). In multiple linear regression analysis KCNQ1 genotype (p=0.016) and baseline FPG (p<0.001) were the only significant independent predictors of ΔFPG (R2=0.48). CONCLUSIONS: Our results suggest that the magnitude of FPG reduction after 6-month sulphonylurea treatment in addition to metformin in patients with type 2 diabetes is related to the variation in KCNQ1. The FPG response to sulphonylureas was significantly lower in carriers of the risk GG genotype.

KCNQ1 gene polymorphism is associated with glycaemic response to treatment with DPP-4 inhibitors.

AIMS: Only afew gene variants were associated with the response to dipeptidylpeptidase-4 inhibitors (DPP4I). KCNQ1 gene variants were previously related both to type 2 diabetes (T2D) and incretin effect. We hypothesized that T2D related KCNQ1 variants would be associated with smaller glucose-lowering effect of DDP4I. METHODS: We performed a retrospective study in 137 Caucasian subjects with T2D who were followed for 6months after initiation of DPP4I treatment. Genotyping for KCNQ1 rs163184 and rs151290 was performed using PCR-HRMA and PCR-RFLP methods, respectively. The main clinical outcome was reduction in HbA1c (ΔHbA1c) after 6-month DPP4I treatment. RESULTS: KCNQ1 rs163184 T>G variant was associated with the response to DPP4I treatment in genetic additive model (ß=-0.30, p=0.022). For each G allele in the rs163184 genotype, we observed a 0.3% (3.3mmol/mol) less reduction in HbA1c during treatment with a DPP4I. Both the GG homozygotes and G-allele carriers had significantly smaller HbA1c reduction in comparison with the TT homozygotes. CONCLUSIONS: KCNQ1 rs163184 T>G variant was associated with a reduced glycaemic response to DPP4I. The difference of 0.6% (6.5mmol/mol) in HbA1c reduction between the TT and GG homozygotes might be of clinical significance if replicated in further studies.

Association between TCF7L2 Genotype and Glycemic Control in Diabetic Patients Treated with Gliclazide.

Previous studies showed associations between variants in TCF7L2 gene and the therapeutic response to sulfonylureas. All sulfonylureas stimulate insulin secretion by the closure of ATP-sensitive potassium (KATP) channel. The aim of the present study was to compare TCF7L2 genotype specific effect of gliclazide binding to KATP channel A-site (Group 1) with sulfonylureas binding to AB-site (Group 2). A total of 101 patients were treated with sulfonylureas for 6 months as an add-on therapy to the previous metformin treatment. TCF7L2 rs7903146 C/T genotype was identified by real-time PCR with subsequent melting curve analysis. Analyses using the dominant genetic model showed significantly higher effect of gliclazide in the CC genotype group in comparison with combined CT + TT genotype group (1.32 ± 0.15% versus 0.73 ± 0.11%, P (adj) = 0.005). No significant difference in ΔHbA1c between the patients with CC genotype and the T-allele carriers was observed in Group 2. In the multivariate analysis, only the TCF7L2 genotype (P = 0.006) and the baseline HbA1c (P < 0.001) were significant predictors of ΔHbA1c. After introducing an interaction term between the TCF7L2 genotype and the sulfonylurea type into multivariate model, the interaction became a significant predictor (P = 0.023) of ΔHbA1c. The results indicate significantly higher difference in ΔHbA1c among the TCF7L2 genotypes in patients treated with gliclazide than in patients treated with glimepiride, glibenclamide, or glipizide.

KCNJ11 gene E23K variant and therapeutic response to sulfonylureas.

AIMS: Potassium inwardly rectifier 6.2 subunit (Kir6.2) of the ATP-sensitive potassium (K(ATP)) channel encoded by KCNJ11 gene is a therapeutical target for sulfonylureas. KCNJ11 E23K polymorphism was associated with type 2 diabetes in genetic association studies. The aim of the present pharmacogenetic study was to examine the effect of sulfonylurea treatment on glycemic control in relationship to KCNJ11 E23K variant. PATIENTS AND METHODS: One hundred and one patients with type 2 diabetes who failed to achieve HbA1c<7% on previous metformin monotherapy were included to the study. Sulfonylurea drug was given in addition to metformin. The main outcome of the study was reduction in HbA1c level (ΔHbA1c) after 6-month sulfonylurea therapy. KCNJ11 genotypes were determined by real-time PCR with melting curve analysis. RESULTS: After 6-month treatment, KCNJ11 K-allele carriers had higher decrease in HbA1c compared with EE homozygotes in the dominant genetic model (1.04±0.10 vs. 0.79±0.12%, p=0.036). In the log-additive model, greater mean reduction in HbA1c by 0.16% (95% CI 0.01-0.32, p=0.038) per each K-allele was observed. The relationship of treatment response with KCNJ11 genotype was also significant in the biggest subgroup of patients treated with gliclazide (n=55). CONCLUSIONS: Carriers of the KCNJ11 K-allele have better therapeutic response to gliclazide. This observation might help to identify patients who will have the highest benefit from sulfonylurea treatment.

Relationship between type 2 diabetes mellitus and hypothalamic-pituitary-adrenal axis.

INTRODUCTION: Hypercortisolism often leads to impaired glucose tolerance or type 2 diabetes mellitus. On the other hand, changes in the regulation of hypothalamic-pituitary-adrenal axis become a matter of debate in patients with type 2 diabetes mellitus/metabolic syndrome. PATIENTS, MATERIALS, AND METHODS: Authors assessed the hypothalamic-pituitary-adrenal axis activity and subclinical Cushing's syndrome occurrence in 50 patients with type 2 diabetes mellitus in comparison to 25 sex-, age-, and BMI-matched control nondiabetic subjects. 1 mg dexamethasone suppression test with NIH recommended cut-off level for adrenal incidentaloma (serum cortisol after suppression > 138 nmol/l) was used to postulate the diagnosis of subclinical hypercortisolism. RESULTS: There were no significant differences in serum ACTH, DHEA-S, baseline serum cortisol as well as serum cortisol after suppression of 1 mg dexamethasone/subclinical Cushing's syndrome prevalence in both diabetic and control groups (18 vs. 24% respectively, p = 0.54) and there was no relation to the type of treatment (OAD vs. insulin) in group of diabetics. When divided according to age, diabetics older than 60 years suppressed their serum cortisol significantly worse than their age-related controls (99.3 vs. 85.5 nmol/l, p = 0.0001). Furthermore, diabetics did not show an age-related decrease in DHEA-S levels, whereas controls did (r = -0.302, p = 0.033; r = -0.596, p = 0.0017 respectively). Within the group of diabetics, a positive correlation between C-peptide levels and baseline serum cortisol/DHEA-S levels was detected as well (r = 0.445, p = 0.001 and r = 0.339, p = 0.017 respectively). CONCLUSION: Our data show relatively high but comparable lack of cortisol suppression in both diabetic and control groups; however, we consider the subclinical Cushing's syndrome diagnose to be criteria dependent. There is no dependence of type of diabetes treatment (OAD vs. insulin) on HPA axis activity. Our results might indicate the possible role of cortisol in pathogenesis of type 2 diabetes mellitus in patients with metabolic syndrome as well as possible protective role of DHEA-S within the frame of secondary contraregulatory mechanisms aimed to improve insulin sensitivity and reduce the hyperinsulinemia.