Natural supplements in antiphospholipid syndrome: A case for further study.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombotic events and/or pregnancy complications in the presence of persistently positive antiphospholipid antibodies (aPL). Although long-term anticoagulation with vitamin K antagonists is considered standard of care, there is an unmet need for safe therapeutics as primary thromboprophylaxis or adjuncts to standard of care in APS. APS is driven by oxidative stress, procoagulant, proinflammatory and angiogenic pathways. For these reasons there has been an increased interest into the investigation of antithrombotic, anti-inflammatory and anti-oxidant properties of natural supplements in APS. The objective of this review is to summarize the mechanistic, epidemiologic and clinical evidence behind the use of natural supplements in APS, with a specific focus on vitamin D, omega-3 fatty acids, coenzyme Q10, gingerol, and isoquercetin. This review should serve as a compelling argument for the future study of natural supplements in APS.

Risk of thyroid cancer associated with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: A population-based cohort study.

AIMS: To determine the potential association between the use of either glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 (DPP-4) inhibitors, and the risk of thyroid cancer in individuals with type 2 diabetes. MATERIALS AND METHODS: This population-based cohort study used claims data from the Korean National Health Insurance Database, 2014-2020. Two distinct cohorts were established to compare each incretin-based drug with sodium-glucose cotransporter-2 (SGLT2) inhibitors, chosen as active comparators because of their previous non-association with thyroid cancer, and their common usage as add-on therapy to metformin along with GLP-1RAs and DPP-4 inhibitors. The first cohort included 21 722 new users of GLP-1RAs and 326 993 new users of SGLT2 inhibitors, whereas the second cohort included 904 300 DPP-4 inhibitor new users and 112 017 SGLT2 inhibitor new users. The outcome was the time to incident thyroid cancer. Weighted Cox proportional models were used to estimate hazard ratios of thyroid cancer incidence associated with incretin-based drugs of interest. RESULTS: The use of GLP-1RAs was not associated with an increased risk of thyroid cancer (weighted hazard ratio 0.98, 95% confidence interval 0.62-1.53) compared with that of SGLT2 inhibitors. Using DPP-4 inhibitors was also not associated with an increased risk of thyroid cancer (0.95, 0.79-1.14) compared with that of SGLT2 inhibitors. No significant effect modifications were observed across subgroup analyses. Sensitivity analyses, including alternative outcome definition analysis of medullary thyroid cancer, were consistent with the primary analysis results. CONCLUSIONS: GLP-1RAs and DPP-4 inhibitors were not associated with an increased risk of thyroid cancer in individuals with type 2 diabetes.

Association of adverse respiratory events with sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors among patients with type 2 diabetes in South Korea: a nationwide cohort study.

BACKGROUND: Impaired respiratory function remains underrecognized in patients with type 2 diabetes (T2D), despite common pulmonary impairment. Meanwhile, there is little data available on the respiratory effects of sodium glucose cotransporter 2 inhibitors (SGLT2i). Hence, we examined the association between SGLT2i use and the risk of adverse respiratory events in a real-world setting. METHODS: We conducted a population-based, nationwide cohort study using an active-comparator new-user design and nationwide claims data of South Korea from January 2015 to December 2020. Among individuals aged 18 years or older, propensity score matching was done to match each new user of SGLT2is with dipeptidyl peptidase 4 inhibitors (DPP4is), with patients followed up according to an as-treated definition. The primary outcome was respiratory events, a composite endpoint of acute pulmonary edema, acute respiratory distress syndrome (ARDS), pneumonia, and respiratory failure. Secondary outcomes were the individual components of the primary outcome and in-hospital death. Cox models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: Of 205,534 patient pairs in the propensity score matched cohort, the mean age of the entire cohort was 53.8 years and 59% were men, with a median follow-up of 0.66 years; all baseline covariates achieved balance between the two groups. Incidence rates for overall respiratory events were 4.54 and 7.54 per 1000 person-years among SGLT2i and DPP4i users, respectively, corresponding to a rate difference of 3 less events per 1000 person-years (95% CI - 3.44 to - 2.55). HRs (95% CIs) were 0.60 (0.55 to 0.64) for the composite respiratory endpoint, 0.35 (0.23 to 0.55) for acute pulmonary edema, 0.44 (0.18 to 1.05) for ARDS, 0.61 (0.56 to 0.66) for pneumonia, 0.49 (0.31 to 0.76) for respiratory failure, and 0.46 (0.41 to 0.51) for in-hospital death. Similar trends were found across individual SGLT2is, subgroup analyses of age, sex, history of comorbidities, and a range of sensitivity analyses. CONCLUSIONS: These findings suggest a lower risk of adverse respiratory events associated with patients with T2D initiating SGLT2is versus DPP4is. This real-world evidence helps inform patients, clinicians, and guideline writers regarding the respiratory effects of SGLT2i in routine practice.

Safety of sodium-glucose co-transporter-2 inhibitors on amputation across categories of baseline cardiovascular disease and diuretics use in patients with type 2 diabetes.

AIM: To assess the risk of amputation associated with sodium-glucose co-transporter-2 inhibitors (SGLT2is) among patients with type 2 diabetes, across categories of baseline cardiovascular disease (CVD) and diuretic use (DU). MATERIALS AND METHODS: We conducted an active comparator, new-user cohort study using Korea's nationwide claims data (2015-2020). The study cohort consisted of patients with type 2 diabetes who initiated SGLT2is or dipeptidyl peptidase-4 inhibitors (DPP4is). Cohort entry was defined by first prescription date. We then classified patients into four discrete subcohorts based on their baseline status of CVD and DU as (1) CVD+/DU+, (2) CVD+/DU-, (3) CVD-/DU+ and (4) CVD-/DU-. We performed 1:1 propensity score (PS) matching within each cohort and estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of amputation with SGLT2is versus DPP4is using Cox models. RESULTS: We identified 219 900 PS-matched pairs of SGLT2is and DPP4is (CVD+/DU+, n = 11 719; CVD+/DU-, n = 26 092; CVD-/DU+, n = 26 894; and CVD-/DU-, n = 155 195), with well-balanced baseline covariates across all cohorts. Significantly lower risks of amputation with SGLT2is versus DPP4is were found in CVD+/DU+ (HR 0.36, 95% CI 0.14-0.90), CVD+/DU- (0.45, 0.21-0.99) and CVD-/DU- (0.48, 0.33-0.70), but not in CVD-/DU+ (0.54, 0.26-1.12). Consistent trends in estimates were found across various sensitivity analyses. CONCLUSIONS: Initiating SGLT2is against DPP4is did not increase the risk of amputation across patient populations of varying vulnerability. These findings based on routine practice will reassure clinicians of the safety of SGLT2is with regard to amputation risk in selected high-risk patients with type 2 diabetes.

Risk of breakthrough SARS-CoV-2 infection and clinical outcomes among vaccinated patients with type 2 diabetes.

AIM: To explore the risk of breakthrough infection among patients with type 2 diabetes (T2D) and risk of severe clinical outcomes after SARS-CoV-2 infection according to vaccination status. MATERIALS AND METHODS: We conducted a population-based cohort study using South Korea's linked database of nationwide COVID-19 registry and claims data between 2018 and 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breakthrough infections were measured in 1:1 propensity-score (PS)-matched fully vaccinated patients with versus without T2D (full-vaccination cohort), and HRs for all-cause mortality, intensive care unit (ICU) admission/mechanical ventilation (MV) use, and hospitalizations after SARS-CoV-2 infection were measured in 1:1 PS-matched T2D patients with versus without full-vaccination (T2D cohort). RESULTS: After 1:1 PS matching, 2 109 970 patients with and without T2D were identified (age 63.5 years; 50.9% male). Patients with T2D showed an increased risk of breakthrough infections compared to those without T2D (HR 1.10, 95% CI 1.06-1.14). The increased risk of breakthrough infections was more notable among T2D patients receiving insulin treatment. However, the risk of severe COVID-19 outcomes was lower in fully vaccinated T2D patients compared with unvaccinated T2D patients (all-cause mortality: HR 0.54, 95% CI 0.43-0.67; ICU admission/MV use: HR 0.31, 95% CI 0.23-0.41; hospitalization: HR 0.73, 95% CI 0.68-0.78). CONCLUSIONS: While patients with T2D remain a vulnerable population to SARS-CoV-2 infection even after full-vaccination, full-vaccination was associated with a lower risk of adverse clinical outcomes after SARS-CoV-2 infection. These findings support the guidelines recommending patients with T2D as a priority vaccination group.

Tongue necrosis secondary to giant cell arteritis, successfully treated with tocilizumab: a case report.

BACKGROUND: Giant Cell Arteritis (GCA) is a large vessel vasculitis that most commonly presents with headache, scalp tenderness, jaw claudication, and vision changes. Various other, less common, manifestations have been reported in the literature such as scalp and tongue necrosis. Though most patients respond to corticosteroids, some cases of GCA are refractory to the high doses of corticosteroids. CASE PRESENTATION: We present a 73-year-old female with GCA refractory to corticosteroids presenting with tongue necrosis. This patient significantly improved with a dose of tocilizumab, an IL-6 inhibitor. CONCLUSION: To the best of our knowledge, this is the first case report of a patient with refractory GCA presenting with tongue necrosis that had rapid improvement with tocilizumab. Prompt diagnosis and treatment can prevent severe outcomes such as tongue amputation in GCA patients with tongue necrosis, and tocilizumab may be effective for corticosteroid-refractory cases.

Long-term clinical outcomes of oral antidiabetic drugs as fixed-dose combinations: A nationwide retrospective cohort study.

AIM: To compare treatment patterns and clinical outcomes of single-pill fixed-dose combination (FDC) and two-pill combination (TPC) therapies using real-world data. METHODS: We conducted a nationwide retrospective cohort study using South Korea's healthcare database (2002-2015). We identified two cohorts of incident patients with type 2 diabetes who initiated FDC or TPC therapy within 4 months of their first prescription for metformin or sulphonylurea. We examined persistence and adherence patterns and the clinical outcome of a composite endpoint of death or hospitalization for acute myocardial infarction, heart failure or stroke and compared the differences in treatment patterns and clinical outcomes using Cox models. RESULTS: Of 5143 and 10 973 patients who initiated FDC and TPC therapy, respectively, we identified 5143 patient pairs after propensity score matching. The FDC group exhibited greater median time to treatment discontinuation (163 vs. 146 days), and proportion of days covered at 12 months (mean 0.60 vs. 0.57, P < .0001) and at 24 months (0.53 vs. 0.51, P = .014) than the TPC group. The FDC group, compared with the TPC group, had reduced risks of the composite clinical outcome (hazard ratio 0.86, 95% confidence intervals 0.77-0.97) and hospitalization for stroke (0.80, 0.67-0.96). CONCLUSION: FDC therapy may provide favourable cardiovascular benefits, especially reducing the risk of hospitalization for stroke, and has better medication adherence among patients with type 2 diabetes.

A double-blind, placebo-controlled, single-ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue, in healthy subjects.

AIM: To evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue under development, in healthy males and females presenting with no childbearing potential. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled, single-ascending dose study was conducted in 56 subjects who randomly received a single subcutaneous dose of HM15136 or its matching placebo at a ratio of 6:2 at 10, 20, 30, 50, 80, 100, and 120 µg/kg. RESULTS: All adverse events were mild and transient. Neither serious adverse events nor discontinuation as a result of adverse events occurred. The most frequent adverse drug reaction was nausea (5.3%, only in the 100- and 120-µg/kg groups). HM15136, particularly at doses of 50 µg/kg or higher, increased fasting blood glucose, with a maximum increase and area under the curve of 1.5 mmol/L at day 10 (P = .006) and 166.3 day·mmol/L (P = .022) at the dose of 80 µg/kg, while suppressing the secretion of endogenous glucagon, which continued until day 17. HM15136 also significantly reduced gluconeogenic and ketogenic amino acids. Compensatory changes in endogenous insulin and incretin hormones by HM15136 were not apparent. HM15136 was slowly but steadily absorbed and reached a peak concentration at 46-68 hours after a single subcutaneous injection. HM15136 was eliminated with a terminal phase half-life of 77.1-101.1 hours. CONCLUSIONS: A single subcutaneous dose of HM15136 at 10-120 µg/kg was safe and well tolerated. The long half-life of HM15136, coupled with an increase in blood glucose for ~2 weeks, may warrant a weekly dosing regimen.

Sodium-glucose cotransporter-2 inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body-induced NRF2 activation.

AIMS: To evaluate whether sodium-glucose cotransporter-2 (SGLT2) inhibition reduces cellular senescence in the kidney and to investigate the molecular pathways involved in the renoprotective effect. MATERIALS AND METHODS: Dapagliflozin (1 mg/kg), glimepiride (2.5 mg/kg) or vehicle was administered daily via oral gavage for 8 weeks in db/db mice. Expression levels of ageing marker genes (p21, p16, and p53) and oxidative stress were measured in the kidney using real-time RT-PCR, immunohistochemistry, and Western blot analysis. For in vitro analysis, HK-2 cells, a human renal tubular epithelial cell line, were pretreated with H2 O2 to induce cellular senescence, and the levels of ageing markers were measured after treatment with ß-hydroxybutyrate (ß-HB) or NRF2-specific siRNA. RESULTS: Expression levels of ageing marker genes (p21, p16 and p53) and senescence-associated secretory phenotypes of the kidney were increased in the vehicle-treated db/db (db/db + vehicle) group compared with the db/+ group, and this increase was markedly reversed in the dapagliflozin-treated db/db (db/db + SGLT2 inhibitor) group, but not in the glimepiride-treated db/db (db/db + sulphonylurea [SU]) group. In the kidneys of mice in the db/db + SGLT2 inhibitor group, oxidative stress and DNA damage were also reduced compared with those of mice in the db/db + vehicle and db/db + SU groups. Dapagliflozin increased plasma ß-HB, which reduced H2 O2 -induced DNA damage and senescence in HK-2 cells. ß-HB-induced NRF2 nuclear translocation mediated anti-senescent effects by inducing antioxidant pathways. CONCLUSIONS: Dapagliflozin prevented the progression of diabetic kidney disease by inhibiting cellular senescence and oxidative stress via ketone-induced NRF2 activation.

Effect of Changes in Patient's Self-management Strategies on Clinical Outcomes: Evidence from a Cohort Study of Patients with Diabetes, Hypertension, and Hyperlipidemia.

BACKGROUND: Self-management has become the dominant care model for chronic disease management. This study aimed to investigate the effect of changes in self-management strategies on the clinical outcomes of chronic diseases. METHODS: Two hundred ninety-seven patients with one or more chronic disease (diabetes, dyslipidemia, or hypertension) were registered and followed in this prospective cohort study. We compared differences in the changes in clinical outcomes from baseline to 6 months according to the improvement of self-management strategies by analysis of covariance. RESULTS: Diabetic patients with improved self-management strategies showed a significantly greater change in HbA1c levels compared to patients without improvement of self-management strategies (group difference in HbA1c = 0.51%). In hypertensive patients, systolic and diastolic blood pressure (BP) showed a significant decline in the patients with improved self-management strategies (group difference in systolic BP = 6.2 mmHg and in diastolic BP = 5.5 mmHg). Clinical outcomes improved significantly when self-management strategies improved in people with a poor self-management strategy at baseline. CONCLUSIONS: This study suggests that improvements in self-management strategies are associated with an improvement in clinical outcomes among patients with chronic diseases, especially for those with an initially poor self-management strategy.

Efficacy and safety of gemigliptin as add-on therapy to insulin, with or without metformin, in patients with type 2 diabetes mellitus (ZEUS II study).

The objective of this study was to evaluate the efficacy and safety of gemigliptin added to a stable dose of insulin alone or of insulin in combination with metformin in patients with type 2 diabetes mellitus. After a two-week run-in period, patients were randomized 2:1 to receive gemigliptin 50 mg or placebo once daily as add-on to background therapy with insulin or insulin plus metformin for 24 weeks. The primary endpoint was change in haemoglobin A1c (HbA1c) from baseline at Week 24. Baseline characteristics were similar between the gemigliptin (n = 188) and placebo (n = 95) groups in terms of HbA1c (8.1%). At Week 24, the gemigliptin group showed a statistically significant reduction in mean HbA1c from baseline as compared with placebo (between-group mean difference, -0.7% [95% CI, -0.9% to -0.4%]; P-value < 0.0001). The incidence of overall adverse events and the number of hypoglycaemic adverse events were similar between the study groups. Gemigliptin added to insulin alone or to insulin in combination with metformin resulted in superior glycaemic control compared to that in the placebo group and was well tolerated for 24 weeks in patients with type 2 diabetes mellitus, without causing weight gain or increasing the incidence of hypoglycaemia.

Effects of MOTS-c on the mitochondrial function of cells harboring 3243 A to G mutant mitochondrial DNA.

Mitochondrial derived peptides (MDPs) are a class of peptide encoded in small open reading frames of mitochondrial DNA (mtDNA). MOTS-c, a recently discovered MDP, participates in retrograde signaling from the mitochondria to the nucleus to control cellular metabolism. Humanin, another MDP, has cytoprotective properties and enhances mitochondrial function. However, it has not yet been tested whether MOTS-c can affect mitochondrial function. We investigated the effect of exogenous and endogenous MOTS-c on mitochondrial function in a cybrid cell harboring 3243 A to G mutant mtDNA, which causes significant mitochondrial dysfunction. To test the effects of endogenous MOTS-c, the cybrid cell was transfected with a MOTS-c EGFP expression vector. Exogenous (synthetic) MOTS-c did not show a significant effect on the ATP content or the mRNA and protein levels of the mitochondrial complex in the mutant cybrid cells. Basal and stimulated mitochondrial respiration were also not affected by exogenous MOTS-c. The mutant cybrid cells transfected with the MOTS-c EGFP expression vector stably expressed MOTS-c, but ATP production and mRNA and protein levels of the mitochondrial complex were not affected. In contrast to other MDPs, MOTS-c does not improve mitochondrial dysfunction in cybrid cells with mutant mtDNA, which suggests the heterogeneous nature of MDPs.

Efficacy of an Electronic Health Management Program for Patients With Cardiovascular Risk: Randomized Controlled Trial.

BACKGROUND: In addition to medication, health behavior management is crucial in patients with multiple risks of cardiovascular mortality. OBJECTIVE: This study aimed to examine the efficacy of a 3-month Smart Management Strategy for Health-based electronic program (Smart Healthing). METHODS: A 2-arm randomized controlled trial was conducted to assess the efficacy of Smart Healthing in 106 patients with at least one indicator of poor disease control and who had hypertension, diabetes, or hypercholesterolemia. The intervention group (n=53) took part in the electronic program, which was available in the form of a mobile app and a Web-based PC application. The program covered 4 areas: self-assessment, self-planning, self-learning, and self-monitoring by automatic feedback. The control group (n=53) received basic educational material concerning disease control. The primary outcome was the percentage of participants who achieved their clinical indicator goal after 12 weeks into the program: glycated hemoglobin (HbA1c) <7.0%, systolic blood pressure (SBP) <140 mmHg, or low-density lipoprotein cholesterol <130 mg/dL. RESULTS: The intervention group showed a significantly higher success rate (in comparison with the control group) for achieving each of 3 clinical indicators at the targeted goal levels (P<.05). Only the patients with hypertension showed a significant improvement in SBP from the baseline as compared with the control group (72.7% vs 35.7%; P<.05). There was a significant reduction in HbA1c in the intervention group compared with the control group (difference=0.54%; P≤.05). In the intervention group, 20% of patients with diabetes exhibited a ≥1% decrease in HbA1c (vs 0% among controls; P≤.05). CONCLUSIONS: A short-term self-management strategy-based electronic program intervention may improve clinical outcomes among patients with cardiovascular risks. TRIAL REGISTRATION: ClinicalTrials.gov NCT03294044; https://clinicaltrials.gov/ct2/show/NCT03294044.

Fabrication of Silver-Doped (Bi,Sb)2Te3 Thermoelectric Film Prepared from Ag Nanoparticles/Bi-Sb-Te Pastes.

Film-type thermoelectric generator (TEG) utilizing Bi-Te based paste has been highly considered as advanced power sources for the wearable electronic devices due to its light, thin and flexible characteristics when producing electricity from certain thermal resources such as human body heat. However, the application of the film-typed TEG has been often limited due to its low TE conversion efficiency caused by low electrical conductivity resulting from severe porosity. Thus, it is crucial to increase electrical properties via densification of the TE film. Here, we synthesized silver nanoparticle (AgNP)-dispersed (Bi,Sb)2Te3 (BSbT) powders to fabricate AgNP-BSbT pastes by adding organic binder. The synthesized AgNP-BSbT pastes were printed through a hand-painting process and were consolidated into Ag-doped BSbT (Ag-BSbT) thick film with a few hundreds µm with controlled 2-step heat treatment. The microstructures of Ag-BSbT films show abnormally elongated grains but also the amount of porosities in the film significantly decreased by addition of AgNP. As a result, it is confirmed that the 0.072 at% Ag-BSbT thick film exhibits power factor of 2.93 × 10-3 W/mK² at room temperature, which is comparable to that of practically utilized bulk materials. It is elucidated that the increase in power factor originates from the modulation between electrical conductivity and Seebeck coefficients due to increased hole carrier density at room temperature.

Sodium-glucose cotransporter-2 inhibition improves incretin sensitivity of pancreatic ß-cells in people with type 2 diabetes.

AIM: To test the hypothesis that dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, improves ß-cell responses to incretin hormones (or ß-cell incretin sensitivity) by alleviating glucose toxicity in people with type 2 diabetes mellitus (T2DM). METHODS: A total of 19 people with T2DM underwent a 3-hour hyperglycaemic clamp study with incretin infusion before and after 8-week treatment with dapagliflozin added to the background treatment. In addition, 10 people with normal glucose tolerance (NGT) underwent a single hyperglycaemic clamp study. The hyperglycaemic clamp was targeted at 15.5 mmol/L for 3 hours, with synthetic glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) infusion over a 60- to 180-minute and a 120- to 180-minute period, respectively. RESULTS: Compared with baseline, the C-peptide response to GLP-1 (incremental area under the curve [iAUC] of C-peptide60-120 minutes ) significantly increased (83.6 ± 42.1 to 106.6 ± 45.7 nmol/L × min; P = .011), and the C-peptide response to GIP/GLP-1 (iAUC of C-peptide120-180 minutes ) tended to increase after dapagliflozin treatment (82.5 ± 58.4 to 101.9 ± 50.3 nmol/L × min; P = .087), whereas both the insulin responses to GLP-1 and GIP/GLP-1 increased significantly. First-phase C-peptide response, which reflects ß-cell function, significantly increased after dapagliflozin treatment; however, all these improved values in the participants with T2DM were far lower than those in the participants with NGT. In addition, the improvement in insulin responses to hyperglycaemia was correlated with the improvement in insulin responses to incretin infusion. CONCLUSIONS: Dapagliflozin improved ß-cell responses to incretin hormones as well as glucose during the hyperglycaemic clamp in patients with inadequately controlled T2DM.

Efficacy and safety of dulaglutide monotherapy compared with glimepiride in East-Asian patients with type 2 diabetes in a multicentre, double-blind, randomized, parallel-arm, active comparator, phase III trial.

AIMS: To compare the efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide 1.5 and 0.75 mg with glimepiride in East-Asian patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In this phase III, multinational, multicentre, double-blind, randomized, parallel-arm, 26-week study, patients with inadequate glycaemic control were randomized 1:1:1 to once-weekly dulaglutide 1.5 or 0.75 mg or daily glimepiride (1-3 mg/d). The primary endpoint was assessment of the non-inferiority of dulaglutide (1.5 mg), as measured by change in glycated haemoglobin (HbA1c), compared with glimepiride using a 0.4% non-inferiority margin. RESULTS: A total of 737 patients were randomized (dulaglutide 1.5 mg, n = 244; dulaglutide 0.75 mg, n = 248; glimepiride, n = 245). At week 26, both doses of dulaglutide were non-inferior and also superior to glimepiride for HbA1c reduction from baseline with a least squares mean difference of -6.34 mmol/mol (95% confidence interval [CI] -8.31, -4.26) or -0.58% (95% CI -0.76, -0.39) for dulaglutide 1.5 mg and -3.50 mmol/mol (95% CI -5.47, -1.42) or -0.32% (95% CI -0.50, -0.13) for dulaglutide 0.75 mg (P < .001). A greater proportion of patients in the dulaglutide 1.5 mg group achieved the HbA1c target of <53 mmol/mol (<7.0%) compared with the glimepiride group (74.1% vs 57.4%; P < .001). The mean body weight decreased (P < .005) and total hypoglycaemia rates were lower (P < .001) in the dulaglutide groups compared with the glimepiride group. The most common drug-related adverse events in both dulaglutide groups (≥5% of patients) included diarrhoea, nausea, increased lipase, decreased appetite, abdominal distension and vomiting. CONCLUSIONS: Dulaglutide (both doses) demonstrated superior glycaemic control vs glimepiride, with a favourable tolerability and safety profile in East-Asian patients with T2D.

Fimasartan increases glucose-stimulated insulin secretion in patients with type 2 diabetes and hypertension compared with amlodipine.

AIM: To study the effects of angiotensin receptor blockers (ARBs) on insulin secretion in hypertensive patients with type 2 diabetes. MATERIALS AND METHODS: A total of 41 patients were enrolled in this open-label, active comparator-controlled, crossover study. After a 2-week run-in period with amlodipine, the participants were assigned to receive either fimasartan (60-120 mg daily) or amlodipine (5-10 mg daily) for 16 weeks. Thereafter, they were treated with the other drug for another 16 weeks. Physical examinations and laboratory tests were performed before and after each treatment. RESULTS: Blood pressure, glycated haemoglobin and oral glucose tolerance test (OGTT) values were similar with each treatment. Fimasartan treatment significantly increased median (range) homeostatic assessment of ß-cell function values (49.9 [22.5-174.4] vs 46.9 [15.6-148.0]), area under the curve of insulin during OGTT (27 284 [9501-94 525] vs 26 818 [8112-76 704] pmol/L × min), insulinogenic index at 60 minutes (19.7 [3.0-131.2] vs 15.0 [2.4-103.8] pmol/mmol) and at 120 minutes (19.1 [1.9-85.5] vs 12.6 [-4.3-178.8] pmol/mmol) compared with those with amlodipine (all P < .05); however, acute insulin response and insulin resistance indices were similar for both agents. CONCLUSIONS: Compared with amlodipine, fimasartan increased late-phase glucose-stimulated insulin secretion in patients with type 2 diabetes and hypertension. This finding suggests that ARBs would be more beneficial in such patients compared with other classes of anti-hypertensives.

Effect and Mechanisms of Diabetes Resolution According to the Range of Gastric Resection and the Length of Anastomosis in Animal Models: Implication for Gastric Cancer Surgery in Patients with Diabetes Mellitus.

BACKGROUND: To examine the effect and mechanism of Roux-en-Y gastric bypass (RYGB) on the improvement of diabetes according to the length of anastomosis and the gastric pouch volume in an animal model. METHODS: Glucose intolerance was induced with a high-fat diet for 3 months in Sprague-Dawley rats. The animals were subjected to conventional RYGB (cRYGB; 5% gastric pouch with 15-cm Roux limb, 40-cm biliopancreatic limb; n = 9), short-limb RYGB (sRYGB; 5%, 8, 4 cm; n = 9), fundus-sparing RYGB (fRYGB; 30%, 8, 4 cm; n = 9), or sham operation (n = 9). After 6 weeks, oral glucose tolerance tests (OGTTs) were performed, and gut hormones including insulin, total GLP-1, GIP, and ghrelin were analyzed. RESULTS: The cRYGB group showed significantly decreased food intake, body weight, and random glucose (p < 0.05). sRYGB resulted in a similar change of body weight loss to that of cRYGB, but with no improvement of hyperglycemia. The fRYGB group showed similar changes of body weight and random glucose to those of the sham group. In cRYGB and sRYGB, the level of insulin steeply increased until 30 min during OGTT. GLP-1 was higher at 30 min in cRYGB than in other groups, without significance. The fRYGB group showed a slowly increasing pattern in OGTT and GLP-1, and the lowest peak point in insulin and GIP. CONCLUSION: cRYGB with 95% gastric resection was needed to achieve not only weight loss but also diabetes improvement, which could be related to the increase in GLP-1.

Glucagon-like peptide-1: glucose homeostasis and beyond.

Glucagon-like peptide-1 (GLP-1), an incretin hormone secreted primarily from the intestinal L-cells in response to meals, modulates nutrient homeostasis via actions exerted in multiple tissues and cell types. GLP-1 and its analogs, as well as compounds that inhibit endogenous GLP-1 breakdown, have become an effective therapeutic strategy for many subjects with type 2 diabetes. Here we review the discovery of GLP-1; its synthesis, secretion, and elimination from the circulation; and its multiple pancreatic and extrapancreatic effects. Finally, we review current options for GLP-1-based diabetes therapy, including GLP-1 receptor agonism and inhibition of GLP-1 breakdown, as well as the benefits and drawbacks of different modes of therapy and the potential for new therapeutic avenues.