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Circulation Mar 2024Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study).
METHODS
A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups.
RESULTS
We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54-0.91]; =0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55-0.90]; =0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28-0.86]; =0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13-2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24-2.48]).
CONCLUSIONS
This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794143.
Topics: Adult; Aged; Humans; Middle Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucose; Heart Failure; Hypoglycemic Agents; Liraglutide; Myocardial Infarction; Sitagliptin Phosphate; Stroke; Sulfonylurea Compounds
PubMed: 38344820
DOI: 10.1161/CIRCULATIONAHA.123.066604 -
Bioorganic Chemistry Mar 2024Glycerophosphodiester phosphodiesterase (GDPD) is a highly conserved enzyme in both prokaryotic and eukaryotic organisms. It catalyses the hydrolysis of various...
Biochemical evaluation and ligand binding studies on glycerophosphodiester phosphodiesterase from Staphylococcus aureus using STD-NMR spectroscopy and molecular docking analysis.
Glycerophosphodiester phosphodiesterase (GDPD) is a highly conserved enzyme in both prokaryotic and eukaryotic organisms. It catalyses the hydrolysis of various glycerophosphodiesters into glycerol-3-phosphate and corresponding alcohols, which serve as building blocks in several biosynthetic pathways. This enzyme is a well-known virulence factor in many pathogenic bacteria, including Staphylococcus aureus, and is thus considered a potential drug target. In this study, competent E. coli BL21(DE3)pLysS expression cells were used to express the GDPD enzyme from vancomycin-resistant Staphylococcus aureus (VRSA), which was then purified using size exclusion and anion exchange chromatography. The hydrolytic activity of GDPD was evaluated on the non-physiological substrate bis(p-nitrophenyl) phosphate (BpNPP), which indicated functional activity of the enzyme. 79 drugs were evaluated for their inhibitory potential against GDPD enzyme by the colorimetric assay. Out of 79 drugs, 13 drugs, including tenofovir (1), adenosine (2), clioquinol (11), bromazepam (12), lamotrigine (13), sulfadiazine (14), azathioprine (15), nicotine (16), sitagliptin PO (17), doxofylline (18), clindamycin phosphate (19), gentamycin sulphate (20), and ceftriaxone sodium (21) revealed varying degrees of inhibitory potential with IC values in the range of 400 ± 0.007-951 ± 0.016 µM. All drugs were also evaluated for their binding interactions with the target enzyme by saturation transfer difference (STD-NMR) spectroscopy. 10 drugs demonstrated STD interactions and hence, showed binding affinity with the enzyme. Exceptionally, tenofovir (1) was identified to be a better inhibitor with an IC value of 400 ± 0.007 µM, as compared to the standard EDTA (ethylenediaminetetraacetic acid) (IC = 470 ± 0.008 µM). Moreover, molecular docking studies have identified key interactions of the ligand (tenofovir) with the binding site residues of the enzyme.
Topics: Escherichia coli; Ligands; Magnetic Resonance Spectroscopy; Methicillin-Resistant Staphylococcus aureus; Molecular Docking Simulation; Phosphates; Phosphoric Diester Hydrolases; Staphylococcus aureus; Tenofovir; Adenosine; Bromazepam
PubMed: 38335754
DOI: 10.1016/j.bioorg.2024.107153 -
Cardiovascular Diabetology Feb 2024SGLT2 inhibitors and DPP4 inhibitors have been suggested to affect lipid metabolism. However, there are few randomized controlled trials comparing the effects on the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
SGLT2 inhibitors and DPP4 inhibitors have been suggested to affect lipid metabolism. However, there are few randomized controlled trials comparing the effects on the lipid metabolism between the two types of antidiabetic drugs. The SUCRE study (UMIN ID: 000018084) was designed to compare the effects of ipragliflozin and sitagliptin on serum lipid and apolipoprotein profiles and other clinical parameters.
METHODS
This is a multicenter, open-label, randomized, controlled trial. Patients with type 2 diabetes (20-74 years old) with HbA1c levels of 7.0-10.5% and serum triglyceride levels of 120-399 mg/dL (1.35-4.50 mmol/L) on diet and/or oral hypoglycemic agents were enrolled. Subjects were randomized to treatment with ipragliflozin (50 mg/day, n = 77) or sitagliptin (50 mg/day, n = 83). Laboratory measurements were performed at 0, 1, 3, and 6 months of treatment.
RESULTS
Ipragliflozin and sitagliptin reduced fasting plasma glucose, glycoalbumin, and HbA1c almost equally. Ipragliflozin increased HDL-C and decreased apo E. Sitagliptin decreased TG, apo B48, CII, and CIII, but increased LDL-C. The between-treatment differences were significant for HDL-C (P = 0.02) and apo B48 (P = 0.006), and nearly significant for apo A1 (P = 0.06). In addition, ipragliflozin reduced body weight, blood pressure, serum liver enzymes, uric acid, and leptin, and increased serum ketones compared with sitagliptin.
CONCLUSIONS
While ipragliflozin and sitagliptin showed similar effects on glycemic parameters, the effects on serum lipid and apolipoprotein profiles were different. Ipragliflozin may have an anti-atherogenic effect through modulation of HDL-C and apo E compared to sitagliptin through TG and apo B48, CII, and CIII in patients with type 2 diabetes.
Topics: Adult; Aged; Humans; Middle Aged; Young Adult; Apolipoproteins; Apolipoproteins E; Blood Glucose; Diabetes Mellitus, Type 2; Glucosides; Glycated Hemoglobin; Hypoglycemic Agents; Sitagliptin Phosphate; Thiophenes
PubMed: 38331780
DOI: 10.1186/s12933-024-02149-7 -
Diabetes May 2024Dipeptidyl peptidase 4 (DPP-4) and neprilysin (NEP) rapidly degrade glucagon-like peptide 1 (GLP-1) in mice. Commercially available sandwich ELISA kits may not...
Dipeptidyl peptidase 4 (DPP-4) and neprilysin (NEP) rapidly degrade glucagon-like peptide 1 (GLP-1) in mice. Commercially available sandwich ELISA kits may not accurately detect the degradation products, leading to potentially misleading results. We aimed to stabilize GLP-1 in mice, allowing reliable measurement with sensitive commercially available ELISA kits. Nonanesthetized male C57Bl/6JRj mice were subjected to an oral glucose tolerance test (OGTT; 2 g/kg glucose), and plasma total and intact GLP-1 were measured (Mercodia and Alpco ELISA kits, respectively). No GLP-1 increases were seen in samples taken beyond 15 min after the glucose load. Samples taken at 5 and 10 min after the OGTT showed a minor increase in total, but not intact, GLP-1. We then administered saline (control), or a DPP-4 inhibitor (valine pyrrolidide or sitagliptin) with or without an NEP-inhibitor (sacubitril), 30 min before the OGTT. In the inhibitor groups only, intact GLP-1 increased significantly during the OGTT. After injecting male C57Bl/6JRj mice with a known dose of GLP-1(7-36)NH2, peak GLP-1 levels were barely detectable after saline but were 5- to 10-fold higher during sitagliptin and the combination of sitagliptin/sacubitril. The half-life of the GLP-1 plasma disappearance increased up to sevenfold during inhibitor treatment. We conclude that reliable measurement of GLP-1 secretion is not possible in mice in vivo with commercially available sandwich ELISA kits, unless degradation is prevented by inhibition of DPP-4 and perhaps NEP. The described approach allows improved estimates of GLP-1 secretion for future studies, although it is a limitation that these inhibitors additionally influence levels of insulin and glucagon.
Topics: Male; Mice; Animals; Glucagon-Like Peptide 1; Blood Glucose; Dipeptidyl Peptidase 4; Glucose; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate; Aminobutyrates; Biphenyl Compounds
PubMed: 38295385
DOI: 10.2337/db23-0848 -
Diabetes & Metabolism Journal Mar 2024We investigated the long-term efficacy and safety of initial triple therapy using metformin, a dipeptidyl peptidase-4 inhibitor, and a sodium-glucose cotransporter-2...
BACKGRUOUND
We investigated the long-term efficacy and safety of initial triple therapy using metformin, a dipeptidyl peptidase-4 inhibitor, and a sodium-glucose cotransporter-2 inhibitor, in patients with type 2 diabetes mellitus.
METHODS
We enrolled 170 drug-naïve patients with glycosylated hemoglobin (HbA1c) level >7.5% who had started triple therapy (metformin, sitagliptin, and empagliflozin). Glycemic, metabolic, and urinary parameters were measured for 24 months.
RESULTS
After 24 months, HbA1c level decreased significantly from 11.0%±1.8% to 7.0%±1.7%. At 12 and 24 months, the rates of achievement of the glycemic target goal (HbA1c <7.0%) were 72.5% and 61.7%, respectively, and homeostasis model assessment of β-cell function and insulin resistance indices improved. Whole-body fat percentage decreased by 1.08%, and whole-body muscle percentage increased by 0.97% after 24 months. Fatty liver indices and albuminuria improved significantly. The concentration of ketone bodies was elevated at the baseline but decreased after 24 months. There were no serious adverse events, including ketoacidosis.
CONCLUSION
Initial triple combination therapy with metformin, sitagliptin, and empagliflozin led to achievement of the glycemic target goal, which was maintained for 24 months without severe hypoglycemia but with improved metabolic function and albuminuria. This combination therapy may be a good strategy for drug-naïve patients with type 2 diabetes mellitus.
Topics: Humans; Diabetes Mellitus, Type 2; Metformin; Sitagliptin Phosphate; Glycated Hemoglobin; Sodium-Glucose Transporter 2 Inhibitors; Albuminuria; Blood Glucose; Treatment Outcome; Benzhydryl Compounds; Glucosides
PubMed: 38273791
DOI: 10.4093/dmj.2023.0128 -
Pakistan Journal of Pharmaceutical... Nov 2023Pharmaceutical substance sitagliptin has long been used to treat diabetes. However, subsequent researches have shown that sitagliptin has additional therapeutic effects....
Pharmaceutical substance sitagliptin has long been used to treat diabetes. However, subsequent researches have shown that sitagliptin has additional therapeutic effects. Anti-inflammatory effects are observed. Combining sitagliptin with biodegradable polymers like nanoparticles for chemotherapy may be effective. This method enhances therapeutic agent pharmacokinetics. This study tests sitagliptin (SIT) chitosan base nanoparticles against MCF-7 cancer cell lines for anti-cancer effects. Sitagliptin chitosan-based nanoparticles are tested for their ability to suppress MCF-7 cancer cell proliferation. Ionic gelation, a typical nanoparticle manufacturing method, was used. A detailed examination of the nanoparticles followed, using particle-size measurement, FTIR and SEM. Entrapment efficiency, drug-loading, and in-vitro drug release were assessed. Loaded with chitosan and sitagliptin, the nanoparticles averaged 500nm and 534nm in diameter. Sitagliptin has little effect on particle size. Chitosan-based Sitagliptin nanoparticles grew slightly, suggesting Sitagliptin is present. SIT-SC-NPs had 32% encapsulation efficiency and 30% drug content due to their high polymer-to-drug ratio. SEM analysis showed that both drug-free and sitagliptin-loaded nanoparticles are spherical, as shown by the different bands in the photos. The SIT-CS-NPs had a 120-hour release efficiency of up to 80%. This suggests that these nanoparticles could cure hepatocellular carcinoma, specifically MCF-7 cell lines.
Topics: Humans; Sitagliptin Phosphate; Chitosan; MCF-7 Cells; Antineoplastic Agents; Nanoparticles; Polymers; Liver Neoplasms
PubMed: 38264890
DOI: No ID Found -
European Heart Journal Apr 2024
Topics: Humans; Diabetes Mellitus, Type 2; Sitagliptin Phosphate; Comparative Effectiveness Research; Cohort Studies; Heart Failure; Glucose; Sodium
PubMed: 38252975
DOI: 10.1093/eurheartj/ehad866 -
Diabetes, Obesity & Metabolism Apr 2024This study aimed to assess the efficacy and safety of prusogliptin (DBPR108), a novel and highly selective dipeptidyl peptidase-4 inhibitor, in individuals with type 2... (Randomized Controlled Trial)
Randomized Controlled Trial
AIM
This study aimed to assess the efficacy and safety of prusogliptin (DBPR108), a novel and highly selective dipeptidyl peptidase-4 inhibitor, in individuals with type 2 diabetes who had not been using glucose-lowering agents regularly for the 8 weeks before the screening period.
MATERIALS AND METHODS
In this multicentre, randomized, double-blind, phase 3 study, adult patients with type 2 diabetes were randomly assigned to receive either DBPR108 100 mg, sitagliptin 100 mg, or placebo once daily during the initial 24-week double-blind treatment period, followed by a 28-week open-label extension period during which all patients received DBPR108 100 mg once daily. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) levels from baseline to week 24.
RESULTS
In total, 766 patients were enrolled and received DBPR108 100 mg (n = 462), sitagliptin 100 mg (n = 152), or placebo (n = 152). The mean age of all patients was 54.3 ± 10.5 years, with 58% being men. The median duration of type 2 diabetes was 0.38 (0.02, 2.65) years, and the mean HbA1c (SD) at baseline was 7.94% (0.62), 7.88% (0.61) and 7.83% (0.59) for DBPR108, sitagliptin and placebo groups, respectively. At week 24, the least square mean (SE) changes from baseline in HbA1c were -0.63% (0.04%) for DBPR108, -0.60% (0.07%) for sitagliptin and -0.02% (0.07%) for placebo. The mean treatment difference between DBPR108 and placebo was -0.61% (95% CI -0.77% to -0.44%), and between DBPR108 and sitagliptin was -0.03% (95% CI -0.19% to 0.13%). These results indicate that DBPR108 was superior to placebo and non-inferior to sitagliptin. DBPR108 also significantly reduced fasting and postprandial plasma glucose levels and had little effect on body weight. The mean (SD) changes in HbA1c from baseline to week 52 were -0.50% (0.97%) for the DBPR108 group, -0.46% (0.96%) for the sitagliptin group and -0.41% (0.95%) for the placebo group. The incidence of adverse events was comparable across all three groups.
CONCLUSIONS
DBPR108 showed superiority to placebo and non-inferiority to sitagliptin in terms of glycaemic control over the initial 24 weeks in treatment-naïve patients with type 2 diabetes. Furthermore, its efficacy was sustained for up to 52 weeks.
Topics: Male; Adult; Humans; Middle Aged; Female; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Drug Therapy, Combination; Hypoglycemic Agents; Sitagliptin Phosphate; Treatment Outcome; Double-Blind Method; Metformin; Butanes; Nitriles; Pyrrolidines
PubMed: 38221859
DOI: 10.1111/dom.15433 -
The Journal of Dermatology Jun 2024A 73-year-old man with diabetes mellitus was referred to our department for ultraviolet treatment for erythematous skin lesions with itching. On dipeptidyl peptidase-4...
A 73-year-old man with diabetes mellitus was referred to our department for ultraviolet treatment for erythematous skin lesions with itching. On dipeptidyl peptidase-4 inhibitor (DPP-4i) sitagliptin (Januvia®) for diabetes mellitus, the erythematous skin lesions appeared and spread to the whole body. At the initial visit, erythema multiforme-like skin lesions with crusts were observed on the trunk and extremities, and the patient was suspected to have drug eruption. Histopathology demonstrated eosinophilic infiltration in the superficial dermis and inflammatory cell infiltration in the epidermis. Sitagliptin was discontinued, and erythematous lesions improved with oral prednisolone. Thereafter the patient was treated with phototherapy and betamethasone sodium phosphate infusion for residual prurigo. However, blistering skin lesions appeared 5 months later. Histopathological findings were subepidermal blisters with eosinophilic abscess, and bullous pemphigoid was suspected. CLEIAs for autoantibodies to desmoglein 1 (Dsg1), Dsg3 and BP180 were negative. Direct immunofluorescence showed linear depositions of immunoglobulin G (IgG) and C3 at the epidermal basement membrane zone, and indirect immunofluorescence detected IgG anti-epidermal basement membrane zone antibodies, reacting with the dermal side of 1M NaCl-split normal human skin. IgG antibodies reacted with 200 kDa laminin γ1 (p200) by immunoblotting using dermal extracts. These results indicated that this patient was diagnosed with anti-laminin γ1 (p200) pemphigoid developed after DPP-4i administration. Although reports of DPP-4i-related bullous pemphigoid have accumulated, cases of anti-laminin γ1 (p200) pemphigoid developed after DPP-4i administration are rarely reported.
Topics: Humans; Male; Aged; Dipeptidyl-Peptidase IV Inhibitors; Pemphigoid, Bullous; Laminin; Autoantibodies; Sitagliptin Phosphate; Skin; Drug Eruptions; Prednisolone; Diabetes Mellitus, Type 2
PubMed: 38214494
DOI: 10.1111/1346-8138.17105 -
Diabetes Care Apr 2024To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and β-cell function.
RESEARCH DESIGN AND METHODS
In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting β-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test β-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of β-cell function.
RESULTS
HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P < 0.001], while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride [1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001]. After adjustment for HOMA2-%S to obtain an estimate of β-cell function, the nature of the change in β-cell responses reflected those in β-cell function.
CONCLUSIONS
The differential long-term effects on insulin sensitivity and β-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of β-cell function in the progression of type 2 diabetes.
Topics: Humans; Diabetes Mellitus, Type 2; Insulin Glargine; Hypoglycemic Agents; Glucose; Liraglutide; Insulin Resistance; C-Peptide; Blood Glucose; Metformin; Sitagliptin Phosphate; Sulfonylurea Compounds
PubMed: 38211595
DOI: 10.2337/dc23-1070