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Effects of Basal Insulin on Lipid Profile Compared to Other Classes of Antihyperglycemic Agents in Type 2 Diabetic Patients.
Rigato, M, Avogaro, A, Vigili de Kreutzenberg, S, Fadini, GP
The Journal of clinical endocrinology and metabolism. 2020;(7)
Abstract
OBJECTIVE The lipid profile represents a driver of cardiovascular risk in type 2 diabetes. The effect of chronic insulin therapy on cholesterol levels is unclear. We aim to evaluate the effect of basal insulin on lipid profile compared to other classes of antihyperglycemic agents in type 2 diabetic patients. DESIGN We performed a meta-analysis of randomized controlled trials reporting changes of lipid parameters in type 2 diabetic patients randomly assigned to basal insulin or other classes of anti-hyperglycemic agents. RESULTS The levels of total (TC) and low-density lipoprotein cholesterol (LDL-C) appeared to be significantly reduced by therapies with glucagon-like peptide-1 receptor agonists (GLP-1RA) in comparison to basal insulin (mean difference [MD] -3.80; 95% CI [-6.30 to -1.30] mg/dL, P < .001 and -4.17; 95% CI [-6.04 to -2.30] mg/dL, P < .0001), whereas no difference was detected between basal insulin and dipeptidyl peptidase-4 inhibitors (DPP4-I) or standard therapy (sulfonylurea ± metformin). Thiazolidinediones (TZD) produced a significant improvement in high-density lipoprotein cholesterol (HDL-C) (MD 3.55; 95% CI: 0.55 to 6.56 mg/dL, P = .02) but were associated with an increase in TC and LDL-C (MD 16.20; 95% CI: 9.09 to 23.31 mg/dL, P < .001 and 5.19: 95% CI: -3.00 to 13.39 mg/dL, P = .21). Basal insulin was superior to standard therapy in triglyceride reduction (MD 3.8; 95% CI: 0.99 to 6.63 mg/dL, P = .008). CONCLUSIONS GLP-1RA were superior to basal insulin in the control of TC and LDL-C. Basal insulin effectively reduced serum triglycerides. TZD led to improvement in HDL-C. DPP4-I and standard therapy did not have any significant effect on lipid levels.
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Unravelling the utility of modern sulfonylureas from cardiovascular outcome trials and landmark trials: expert opinion from an international panel.
Kalra, S, Ghosh, S, Das, AK, Nair, T, Bajaj, S, Priya, G, Mehrotra, RN, Das, S, Shah, P, Deshmukh, V, et al
Indian heart journal. 2020;(1):7-13
Abstract
AIM: The primary objective of this review is to develop practice-based expert group opinions on the cardiovascular (CV) safety and utility of modern sulfonylureas (SUs) in cardiovascular outcome trials (CVOTs). BACKGROUND The United States Food and Drug Administration issued new guidance to the pharmaceutical industry in 2008 regarding the development of new antihyperglycemic drugs. The guidance expanded the scope for the approval of novel antihyperglycemic drugs by mandating CVOTs for safety. A few long-term CVOTs on dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors have been completed, while others are ongoing. SUs, which constitute one of the key antihyperglycemic agents used for the management of type 2 diabetes mellitus (T2DM), have been used as comparator agents in several CVOTs. However, the need for CVOTs on modern SUs remains debatable. In this context, a multinational group of endocrinologists convened for a meeting and discussed the need for CVOTs of modern SUs to evaluate their utility in the management of patients with T2DM. At the meeting, CVOTs of modern SUs conducted to date and the hypotheses derived from the results of these trials were discussed. REVIEW RESULTS The expert group analyzed the key trials emphasizing the CV safety of modern SUs and also reviewed the results of various CVOTs in which modern SUs were used as comparators. Based on literature evidence and individual clinical insights, the expert group opined that modern SUs are cardiosafe and that since they have been used as comparators in other CVOTs, CVOTs of SUs are not required. CONCLUSION Modern SUs can be considered a cardiosafe option for the management of patients with diabetes mellitus and CV disease; thus CVOTs among individuals with T2DM are not required.
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Second-Generation Antidiabetic Sulfonylureas Inhibit Candida albicans and Candidalysin-Mediated Activation of the NLRP3 Inflammasome.
Lowes, DJ, Hevener, KE, Peters, BM
Antimicrobial agents and chemotherapy. 2020;(2)
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Abstract
Repurposing of currently approved medications is an attractive option for the development of novel treatment strategies against physiological and infectious diseases. The antidiabetic sulfonylurea glyburide has demonstrated off-target capacity to inhibit activation of the NLRP3 inflammasome in a variety of disease models, including vaginal candidiasis, caused primarily by the fungal pathogen Candida albicans Therefore, we sought to determine which of the currently approved sulfonylurea drugs prevent the release of interleukin 1β (IL-1β), a major inflammasome effector, during C. albicans challenge of the human macrophage-like THP1 cell line. Findings revealed that the second-generation antidiabetics (glyburide, glisoxepide, gliquidone, and glimepiride), which exhibit greater antidiabetic efficacy than prior iterations, demonstrated anti-inflammatory effects with various degrees of potency as determined by calculation of 50% inhibitory concentrations (IC50s). These same compounds were also effective in reducing IL-1β release during noninfectious inflammasome activation (e.g., induced by lipopolysaccharide [LPS] plus ATP), suggesting that their anti-inflammatory activity is not specific to C. albicans challenge. Moreover, treatment with sulfonylurea drugs did not impact C. albicans growth and filamentation or THP1 viability. Finally, the use of ECE1 and Candidalysin deletion mutants, along with isogenic NLRP3-/- cells, demonstrated that both Candidalysin and NLRP3 are required for IL-1β secretion, further confirming that sulfonylureas suppress inflammasome signaling. Moreover, challenge of THP1 cells with synthetic Candidalysin peptide demonstrated that this toxin is sufficient to activate the inflammasome. Treatment with the experimental inflammasome inhibitor MCC950 led to similar blockade of IL-1β release, suggesting that Candidalysin-mediated inflammasome activation can be inhibited independently of potassium efflux. Together, these results demonstrate that the second-generation antidiabetic sulfonylureas retain anti-inflammatory activity and may be considered for repurposing against immunopathological diseases, including vaginal candidiasis.
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Comparative Effectiveness of SGLT2 Inhibitors, GLP-1 Receptor Agonists, DPP-4 Inhibitors, and Sulfonylureas on Risk of Kidney Outcomes: Emulation of a Target Trial Using Health Care Databases.
Xie, Y, Bowe, B, Gibson, AK, McGill, JB, Maddukuri, G, Yan, Y, Al-Aly, Z
Diabetes care. 2020;(11):2859-2869
Abstract
OBJECTIVE To examine the comparative effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP-1), dipeptidyl peptidase 4 inhibitors (DPP-4), and sulfonylureas on risk of kidney outcomes among people with type 2 diabetes. RESEARCH DESIGN AND METHODS U.S. veterans initiated on SGLT2i (n = 18,544), GLP-1 (n = 23,711), DPP-4 (n = 39,399), or sulfonylureas (n = 134,904) were followed for up to 3 years to evaluate the risk of the composite outcome of estimated glomerular filtration rate (eGFR) decline >50%, end-stage kidney disease (ESKD), or all-cause mortality. Risks were estimated using survival models adjusted for predefined covariates as well as covariates identified by a high-dimensional variable selection algorithm through application of generalized propensity scores. RESULTS Compared with those treated with sulfonylureas, treatment with SGLT2i, GLP-1, and DPP-4 was associated with a lower risk of the composite outcome (hazard ratio 0.68 [95% CI 0.63, 0.74], 0.72 [0.67, 0.77], and 0.90 [0.86, 0.95], respectively). While we did not observe a statistically significant difference in risk between the SGLT2i and GLP-1 arms (0.95 [0.87, 1.04]), both SGLT2i and GLP-1 had a lower risk of the composite outcome than DPP-4 (0.76 [0.70, 0.82] and 0.79 [0.74, 0.85], respectively). Analyses by eGFR category suggested that compared with the sulfonylurea arm, those in the SGLT2i and GLP-1 arms exhibited a lower risk of the composite outcome in all eGFR categories, including eGFR <45 mL/min/1.73 m2. Compared with DPP-4, both SGLT2i and GLP-1 exhibited a reduced risk of the composite outcome in eGFR <90 to ≥60, <60 to ≥45, and <45 mL/min/1.73 m2. CONCLUSIONS In type 2 diabetes, treatment with SGLT2i or GLP-1 compared with DPP-4 or sulfonylureas was associated with a lower risk of adverse kidney outcomes.
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Comparison of the effects of three kinds of glucose-lowering drugs on non-alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open-label, three-arm, active control study.
Kinoshita, T, Shimoda, M, Nakashima, K, Fushimi, Y, Hirata, Y, Tanabe, A, Tatsumi, F, Hirukawa, H, Sanada, J, Kohara, K, et al
Journal of diabetes investigation. 2020;(6):1612-1622
Abstract
AIMS/INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus. MATERIALS AND METHODS We carried out a prospective clinical trial (a randomized and open-label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin (n = 32), pioglitazone (n = 33) or glimepiride (n = 33) group, and the patients took these drugs for 28 weeks. The primary end-point was the change of the liver-to-spleen ratio on abdominal computed tomography. RESULTS There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver-to-spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver-to-spleen ratio were comparable. CONCLUSIONS The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.
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Neonatal diabetes due to potassium channel mutation: Response to sulfonylurea according to the genotype.
Garcin, L, Mericq, V, Fauret-Amsellem, AL, Cave, H, Polak, M, Beltrand, J
Pediatric diabetes. 2020;(6):932-941
Abstract
OBJECTIVE A precision medicine approach is used to improve treatment of patients with monogenic diabetes. Herein, we searched SU efficiency according to the genotype-phenotype correlation, dosage used, and side effects. RESEARCH DESIGN AND METHODS Systematic review conducted according the PRISMA control criteria identifying relevant studies evaluating the in vivo and in vitro sensitivity of ATP-dependent potassium channels according to the characteristics of genetic mutation. RESULTS Hundred and three selected articles with complete data in 502 cases in whom 413 (82.3%) had mutations in KCNJ11 (#64) and 89 in ABCC8 (# 56). Successful transfer from insulin to SU was achieved in 91% and 86.5% patients, respectively, at a mean age of 36.5 months (0-63 years). Among patients with KCNJ11 and ABCC8 mutations 64 and 46 were associated with constant success, 5 and 5 to constant failure, and 10 and 4 to variable degrees of reported success rate, respectively. The glibenclamide dosage required for each genotype ranged from 0.017 to 2.8 mg/kg/day. Comparing both the in vivo and in vitro susceptibility results, some mutations appear more sensitive than others to sulfonylurea treatment. Side effects were reported in 17/103 of the included articles: mild gastrointestinal symptoms and hypoglycaemia were the most common. One premature patient had an ulcerative necrotizing enterocolitis which association with SU is difficult to ascertain. CONCLUSIONS Sulfonylureas are an effective treatment for monogenic diabetes due to KCNJ11 and ABCC8 genes mutations. The success of the treatment is conditioned by differences in pharmacogenetics, younger age, pharmacokinetics, compliance, and maximal dose used.
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Oral antidiabetes agents for the management of inpatient hyperglycaemia: so far, yet so close.
Koufakis, T, Mustafa, OG, Zebekakis, P, Kotsa, K
Diabetic medicine : a journal of the British Diabetic Association. 2020;(9):1418-1426
Abstract
BACKGROUND Hyperglycaemia is an ongoing challenge in hospital settings and is associated with poor outcomes. Current recommendations for the management of inpatient hyperglycaemia suggest insulin as the main glucose-lowering treatment choice and limit the administration of oral antidiabetes agents to a small proportion of cases because of safety concerns. AIM: To present and critically appraise the available evidence on the use of oral antidiabetes agents in the hospital setting and the risk-benefit balance of such an approach in the era of cardiovascular outcomes trials. METHODS PubMed, Embase and Google Scholar databases were searched to identify relevant published work. Available evidence on the efficacy and the safety profile of oral agents in the context of their use in hospitalized individuals are summarized and discussed in this narrative review. RESULTS There is no robust evidence to suggest the use of metformin, thiazolidinediones, sulfonylureas and sodium-glucose co-transporter-2 inhibitors in the hospital setting, although some of their effects on acute outcomes deserve further evaluation in future studies. However, the use of dipeptidyl peptidase-4 inhibitors in inpatients with type 2 diabetes is supported by a few, well-designed, randomized controlled trials. These trials have demonstrated good safety and tolerability profiles, comparable to insulin glucose-lowering efficacy, and a reduction in insulin dose when dipeptidyl peptidase-4 inhibitors are co-administered with insulin, in individuals with mild to moderate hyperglycaemia and a stable clinical condition. CONCLUSION The administration of dipeptidyl peptidase-4 inhibitors to specific groups of inpatients might be a safe and effective alternative to insulin.
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Efficacy and Safety of Pioglitazone versus Glimepiride after Metformin and Alogliptin Combination Therapy: A Randomized, Open-Label, Multicenter, Parallel-Controlled Study.
Kim, JM, Kim, SS, Kim, JH, Kim, MK, Kim, TN, Lee, SH, Lee, CW, Park, JY, Kim, ES, Lee, KJ, et al
Diabetes & metabolism journal. 2020;(1):67-77
Abstract
BACKGROUND There is limited information regarding the optimal third-line therapy for managing type 2 diabetes mellitus (T2DM) that is inadequately controlled using dual combination therapy. This study assessed the efficacy and safety of pioglitazone or glimepiride when added to metformin plus alogliptin treatment for T2DM. METHODS This multicenter, randomized, active-controlled trial (ClinicalTrials.gov: NCT02426294) recruited 135 Korean patients with T2DM that was inadequately controlled using metformin plus alogliptin. The patients were then randomized to also receive pioglitazone (15 mg/day) or glimepiride (2 mg/day) for a 26-week period, with dose titration was permitted based on the investigator's judgement. RESULTS Glycosylated hemoglobin levels exhibited similar significant decreases in both groups during the treatment period (pioglitazone: -0.81%, P<0.001; glimepiride: -1.05%, P<0.001). However, the pioglitazone-treated group exhibited significantly higher high density lipoprotein cholesterol levels (P<0.001) and significantly lower homeostatic model assessment of insulin resistance values (P<0.001). Relative to pioglitazone, adding glimepiride to metformin plus alogliptin markedly increased the risk of hypoglycemia (pioglitazone: 1/69 cases [1.45%], glimepiride: 14/66 cases [21.21%]; P<0.001). CONCLUSION Among patients with T2DM inadequately controlled using metformin plus alogliptin, the addition of pioglitazone provided comparable glycemic control and various benefits (improvements in lipid profiles, insulin resistance, and hypoglycemia risk) relative to the addition of glimepiride.
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Pharmacogenetics of Type 2 Diabetes-Progress and Prospects.
Nasykhova, YA, Tonyan, ZN, Mikhailova, AA, Danilova, MM, Glotov, AS
International journal of molecular sciences. 2020;(18)
Abstract
Type 2 diabetes mellitus (T2D) is a chronic metabolic disease resulting from insulin resistance and progressively reduced insulin secretion, which leads to impaired glucose utilization, dyslipidemia and hyperinsulinemia and progressive pancreatic beta cell dysfunction. The incidence of type 2 diabetes mellitus is increasing worldwide and nowadays T2D already became a global epidemic. The well-known interindividual variability of T2D drug actions such as biguanides, sulfonylureas/meglitinides, DPP-4 inhibitors/GLP1R agonists and SGLT-2 inhibitors may be caused, among other things, by genetic factors. Pharmacogenetic findings may aid in identifying new drug targets and obtaining in-depth knowledge of the causes of disease and its physiological processes, thereby, providing an opportunity to elaborate an algorithm for tailor or precision treatment. The aim of this article is to summarize recent progress and discoveries for T2D pharmacogenetics and to discuss the factors which limit the furthering accumulation of genetic variability knowledge in patient response to therapy that will allow improvement the personalized treatment of T2D.
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Integrated proteomics, metabolomics and physiological analyses for dissecting the toxic effects of halosulfuron-methyl on soybean seedlings (Glycine max merr.).
Li, Y, Zhang, Q, Yu, Y, Li, X, Tan, H
Plant physiology and biochemistry : PPB. 2020;:303-315
Abstract
Halosulfuron methyl (HSM) is a herbicide widely used to control sedge and broad-leaved weeds during crop production, but its environmental residue may damage non-target crops. Here, proteomics and metabolomics methods were used to explore the phytotoxicity mechanisms of HSM against soybean (Glycine max Merr.). Soybean seedlings were exposed to 0.01, 0.05 and 0.5 mg/L HSM for 8 d. The HSM applications significantly reduced chlorophyll and carotenoid contents in HSM-treated seedlings. Additionally, chlorophyll a fluorescence was seriously affected. The glutathione, hydrogen peroxide and malondialdehyde contents, as well as antioxidant enzyme activities, significantly increased in seedlings exposed to HSM. Furthermore, five enzymes involved in the tricarboxylic acid (TCA) cycle, α-ketoglutarate dehydrogenase, isocitrate dehydrogenase, aconitase, malic dehydrogenase and succinate dehydrogenase, were inhibited to varying degrees in HSM-treated seedlings compared with controls. Proteomics results showed multiple differentially abundant proteins involved in chlorophyll synthesis, photosystem processes and chloroplast ATP synthetase were down-regulated. Metabolomics analyses revealed that metabolites involved in the TCA cycle decreased significantly. Moreover, metabolites and proteins related to reactive oxygen species detoxification accumulated. In conclusion, the phytotoxicity mechanisms of HSM against soybean mainly act by damaging the photosynthetic machinery, inhibiting chlorophyll synthesis, interrupting the TCA cycle and causing oxidative stress. These results provide new insights into the toxicity mechanisms of sulfonylurea herbicides against non-target crops.