DPP-4 inhibitor linagliptin ameliorates imiquimod-induced psoriasis-like skin alterations in type 2 diabetic mice by inhibiting the MAPK/NF-κB inflammatory pathway.

Studies have shown that the DPP-4 inhibitor was effective in improving skin damage in patients with psoriasis, but the exact mechanism was not known. To investigate the therapeutic effects of linagliptin in mice with type 2 diabetes mellitus (T2DM) with psoriasis and its possible therapeutic mechanisms. A total of 32 db/db mice and 16 db/m mice were randomly divided into six groups: normal group, psoriasis group, diabetes group, diabetes combined with psoriasis group, linagliptin-treated diabetes group, and linagliptin-treated diabetes combined with psoriasis group. The levels of serum fasting blood glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured; the levels of serum FINS were determined by enzyme-linked immunoassay and the insulin resistance index was calculated. Basic parameters of diabetes, Psoriasis Area and Severity Index, histopathology of skin, the expression of interleukin (IL)-17A, IL-23, IL-22, and tumor necrosis factor (TNF)-α, and expression levels of measuring p-ERK, p-MAPK and p-nuclear factor kappa B (NF-κB) in skin tissues were measured. After treatment with linagliptin, insulin resistance, and TC and TG levels were reduced in mice with T2DM and psoriasis (p < .05). Moreover, the degree of epidermal tissue thickening, number of keratinized layers, and inflammatory cell infiltration were also reduced (p < .05), as well as the expression levels of inflammatory factors: TNF-α, IL-1ß, IL-17A, IL-23, and p-P38/P38, p-ERK/ERK, p-P65/P65 proteins (p < .05). Linagliptin significantly reduced the extent of skin lesions and skin inflammation. The underlying mechanism of this compound may be related to the inhibition of MAPK/NF-κB inflammatory pathways and the consequential improvement of insulin resistance.Significance Statement: In this study, we evaluated the therapeutic effect of the DPP-4 inhibitor linagliptin using a murine model of type 2 diabetes combined with psoriasis, and its potential mechanisms of action were further explored. The results of this study will help to uncover the pathogenesis of type 2 diabetes and psoriasis and, more importantly, provide a theoretical basis for the search for safe and effective drugs in the treatment of this specific patient population.

PTPN14 deficiency alleviates podocyte injury through suppressing inflammation and fibrosis by targeting TRIP6 in diabetic nephropathy.

Diabetic nephropathy (DN) is a common complication of diabetes, and a leading cause of end-stage renal disease. However, the pathogenesis that contributes to DKD is still not fully understood. Protein tyrosine phosphatase non-receptor type 14 (PTPN14), a non receptor tyrosine phosphatase, has numerous cellular events, such as inflammation and cell death. But its potential on DKD has not been investigated yet. In this study, we found that PTPN14 expression was markedly up-regulated in kidney samples of DKD patients, which were confirmed in diabetic mice and were clearly localized in glomeruli. The diabetic mouse model was established using streptozotocin (STZ) in wild type (WT) or PTPN knockout (KO) mice. After, STZ challenge, STZ mice displayed improved kidney functions. The results also showed that STZ-induced histological changes and podocyte injury in renal tissues, which were effectively alleviated by PTPN14 deletion. Moreover, PTPN14 deficiency significantly mitigated inflammatory response and fibrosis in glomeruli of STZ-challenged mice through restraining the activation of nuclear factor-κB (NF-κB) and transforming growth factor (TGF)-ß1 signaling pathways, respectively. The inhibitory effects of PTPN14 suppression on inflammation and fibrosis were confirmed in high glucose (HG)-incubated podocytes. We further found that thyroid receptor interactor protein 6 (TRIP6) expression was dramatically up-regulated in glomeruli of STZ-challenged mice, and was abolished by PTPN14 deletion, which was confirmed in HG-treated podocytes with PTPN14 knockdown. Intriguingly, our in vitro studies showed that PTPN14 directly interacted with TRIP6. Of note, over-expressing TRIP6 markedly abrogated the effects of PTPN14 silence to restrict inflammatory response and fibrosis in HG-incubated podocytes. Taken together, our findings demonstrated that targeting PTPN14 may provide feasible therapies for DKD treatment.

Efficacy and safety of linagliptin as add-on therapy to insulin in Chinese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled trial.

This 24-week, double-blind, placebo-controlled, phase III trial evaluated the efficacy and safety of linagliptin in 206 Chinese patients with inadequately controlled (glycated haemoglobin [HbA1c] 7.5%-10.0%) type 2 diabetes mellitus (T2DM) receiving insulin (basal or premixed) ± metformin. Patients were randomized (1:1) to receive linagliptin 5 mg/d or placebo. The decrease from baseline in HbA1c (primary endpoint) was greater with linagliptin than with placebo (-0.61% vs. -0.20%, adjusted mean difference -0.40%; P = 0.0016). Linagliptin demonstrated significantly greater improvement in 2-hour postprandial glucose (-1.77 mmol/L [-31.95 mg/dL]; P < 0.001), and a numerical reduction in fasting plasma glucose (-0.34 mmol/L [-6.2 mg/dL]; P = 0.2241) versus placebo. Proportionally more patients on linagliptin achieved a HbA1c reduction of ≥0.5% versus those on placebo (odds ratio 2.293, P < 0.01). Adverse events in both groups were similar, with no new safety findings or clinically relevant changes in body weight. Among investigator-defined hypoglycaemic events (linagliptin: 17.3%; placebo: 12.7%; odds ratio 1.48, P = 0.337), none were severe. In Chinese patients with T2DM, linagliptin add-on to insulin improved glycaemic control and was well tolerated, without increased risk of hypoglycaemia or weight gain.

DUAL II China: Superior HbA1c reductions and weight loss with insulin degludec/liraglutide (IDegLira) versus insulin degludec in a randomized trial of Chinese people with type 2 diabetes inadequately controlled on basal insulin.

AIM: To assess the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin degludec (degludec) in Chinese people with type 2 diabetes (T2D) treated with basal insulin. MATERIALS AND METHODS: In DUAL II China, a randomized, double-blinded, multicentre, treat-to-target trial, Chinese adults with T2D and HbA1c of 7.5% or more on basal insulin and metformin, with or without other oral antidiabetic drugs (OADs), were randomized 2:1 to 26 weeks of treatment with either IDegLira (max. dose 50 U degludec/1.8 mg liraglutide) or degludec (max. 50 U/day), respectively, combined with metformin. At 26 weeks, superiority of IDegLira over degludec was assessed for change in HbA1c (primary endpoint), and body weight and number of severe or blood glucose (BG)-confirmed hypoglycaemic episodes (confirmatory secondary endpoints). RESULTS: Overall, 453 participants were randomized to IDegLira (n = 302) or degludec (n = 151). Superiority was confirmed for IDegLira over degludec in HbA1c change (-1.9% vs. -1.0%, respectively, estimated treatment difference [ETD] [95% confidence interval]: -0.92% [-1.09; -0.75], P < .0001), body weight change (-0.7 vs. +0.4 kg, respectively, ETD [95% CI]: -1.08 kg [-1.63; -0.52], P = .0002) and severe or BG-confirmed hypoglycaemia (estimated rate ratio [95% CI]: 0.53 [0.30; 0.94], P = .0297). The odds of achieving HbA1c less than 7.0% without hypoglycaemia and/or weight gain were greater with IDegLira than degludec (P < .0001 for all). Daily insulin dose at 26 weeks was lower for IDegLira (34.3 U) than degludec (37.4 U) (P = .0014). No unexpected safety signals were observed. CONCLUSIONS: IDegLira may be an efficacious and well-tolerated treatment intensification option for Chinese people with T2D uncontrolled on basal insulin and OADs.

Efficacy and safety of insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Chinese adults with type 2 diabetes: A phase III, open-label, 2:1 randomized, treat-to-target trial.

AIMS: To assess the efficacy and safety of twice-daily insulin degludec/insulin aspart (IDegAsp) versus biphasic insulin aspart 30 (BIAsp 30) twice daily, both ± metformin, in Chinese adults (N = 543) with type 2 diabetes (T2D) inadequately controlled on premixed/self-mixed or basal insulin ± metformin. MATERIALS AND METHODS: We conducted a 26-week, phase III, open-label, treat-to-target, 2:1 randomized trial. Hierarchical testing was used with non-inferiority of glycated haemoglobin (HbA1c) change from baseline to week 26 as the primary endpoint and superiority for the confirmatory secondary endpoints which were as follows: change from baseline in fasting plasma glucose (FPG); nocturnal confirmed hypoglycaemic episodes (12:01-5:59 am, inclusive); total confirmed hypoglycaemic episodes (severe or plasma glucose <3.1 mmol/L with/without symptoms); body weight; and percentage of responders (HbA1c <53 mmol/mol [<7.0%]) without confirmed hypoglycaemic episodes. RESULTS: Non-inferiority for change from baseline to week 26 in HbA1c and superiority of IDegAsp twice daily versus BIAsp 30 twice daily for change in FPG, nocturnal confirmed and total confirmed hypoglycaemic episodes, was demonstrated. Estimated rates of nocturnal confirmed and total confirmed hypoglycaemic episodes were 47% and 43% lower, respectively, with IDegAsp twice daily versus BIAsp 30 twice daily. Superiority for change in body weight was not confirmed. Participants were more likely to reach the HbA1c goal of <53 mmol/mol (<7.0%) without confirmed hypoglycaemia with IDegAsp twice daily versus BIAsp 30 twice daily by trial end. No new safety signals were identified. CONCLUSIONS: The efficacy and safety of IDegAsp in Chinese patients with T2D was demonstrated, confirming results from international trials.

Efficacy and safety of lixisenatide in a predominantly Asian population with type 2 diabetes insufficiently controlled with basal insulin: The GetGoal-L-C randomized trial.

AIMS: To assess the effects on glycaemic control of lixisenatide vs placebo as add-on treatment to basal insulin (BI) ± metformin and effects on glycated haemoglobin (HbA1c) reduction in patients with insufficiently controlled type 2 diabetes (T2D). METHODS: Patients (n = 448) with inadequately controlled T2D were randomized (1:1) to lixisenatide or placebo as add-on to BI ± metformin for 24 weeks after an 8-week run-in phase, during which BI was titrated to a target self-monitored plasma glucose (SMPG; 4.4-5.6 mmol/L). The primary endpoint was absolute change in HbA1c from baseline to week 24. Secondary efficacy endpoints included: percentage of responders; changes in 2-hour postprandial plasma glucose (PPG); 7-point SMPG (daily average); body weight (BW); total daily BI dose; fasting plasma glucose; and safety assessments. RESULTS: Baseline demographics were similar in the two treatment groups. After insulin optimization during run-in, lixisenatide was superior to placebo in mean change from baseline (7.9% [standard deviation {s.d.}, 0.66] and 7.9% [0.70], respectively) to week 24 in HbA1c (least squares mean [standard error {s.e.}] change -0.62% [0.09] vs -0.11% [0.09]; P < .0001, respectively) and higher proportions of patients achieved HbA1c targets. Two-hour PPG, daily mean SMPG and mean BW were reduced further and daily BI dose was lower with lixisenatide than placebo (-1.12 kg vs 0.04 kg [P < .0001]; -3.0 U vs -1.9 U [P = .0033], respectively). Treatment-emergent adverse events were greater with lixisenatide than placebo (63.8% vs 40.8%, respectively). The incidence of symptomatic hypoglycaemia was similar (lixisenatide 15.6% vs placebo 13.5%). CONCLUSIONS: In Asian patients insufficiently controlled on BI ± metformin, lixisenatide was superior to placebo in glycaemic control, with a tolerability profile in line with other glucagon-like peptide-1 receptor agonists. CLINICAL TRIAL NUMBER: NCT01632163 (clinicaltrials.gov).

Abnormal subcortical nuclei shapes in patients with type 2 diabetes mellitus.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) increases the risk of brain atrophy and dementia. We aimed to elucidate deep grey matter (GM) structural abnormalities and their relationships with T2DM cognitive deficits by combining region of interest (ROI)-based volumetry, voxel-based morphometry (VBM) and shape analysis. METHODS: We recruited 23 T2DM patients and 24 age-matched healthy controls to undergo T1-weighted structural MRI scanning. Images were analysed using the three aforementioned methods to obtain deep GM structural shapes and volumes. Biochemical and cognitive assessments were made and were correlated with the resulting metrics. RESULTS: Shape analysis revealed that T2DM is associated with focal atrophy in the bilateral caudate head and dorso-medial part of the thalamus. ROI-based volumetry only detected thalamic volume reduction in T2DM when compared to the controls. No significant between-group differences were found by VBM. Furthermore, a worse performance of cognitive processing speed correlated with more severe GM atrophy in the bilateral dorso-medial part of the thalamus. Also, the GM volume in the bilateral dorso-medial part of the thalamus changed negatively with HbA1c. CONCLUSIONS: Shape analysis is sensitive in identifying T2DM deep GM structural abnormalities and their relationships with cognitive impairments, which may greatly assist in clarifying the neural substrate of T2DM cognitive dysfunction. KEY POINTS: • Type 2 diabetes mellitus is accompanied with brain atrophy and cognitive dysfunction • Deep grey matter structures are essential for multiple cognitive processes • Shape analysis revealed local atrophy in the dorso-medial thalamus and caudatum in patients • Dorso-medial thalamic atrophy correlated to cognitive processing speed slowing and high HbA1c. • Shape analysis has advantages in unraveling neural substrates of diabetic cognitive deficits.

[The efficacy and safety of human glucagon-like peptide-1 analogue liraglutide in newly diagnosed type 2 diabetes with glycosylated hemoglobin A1c > 9].

OBJECTIVE: To evaluate the efficacy and safety of human glucagon-like peptide-1 analogue liraglutide in newly diagnosed type 2 diabetes mellitus (T2DM) with glycosylated hemoglobin A1c (HbA1c) > 9%. METHODS: This was an open-labelled, randomized, parallel-group, treat-to-target trial. Newly diagnosed T2DM patients with HbA1c > 9% were enrolled. These patients were treated with metformin with repaglinide and randomized to receive once-daily liraglutide (LIRA, n=25) or the insulin glargine (IGla, n=24) at bedtime. Efficacy and safety were assessed and compared after 18-month treatment. RESULTS: (1) Compared with the baseline, patients with LIRA had significantly reduced mean body weight,BMI and waist circumference (P < 0.01), whereas, the above indexes were increased (P < 0.01) in patients treated with IGla. (2) After 18 months of treatment, fasting plasma glucose (FPG), 2-hour plasma glucose after a 75g oral glucose load (2hPG) and HbA1c were significantly improved in all patients (P < 0.01), with 2hPG, mean blood glucose (MBG), the largest amplitude of glycemic excursions (LAGE), mean amplitude of glycemic excursions (MAGE) were significantly lower in LIRA group than in IGla group (all P < 0.05). (3) HOMA-IR decreased in both groups (P < 0.05). However, ΔI30/ΔG30, AUCCP180 and Matsuda index were only significantly increased in patients treated with LIRA (respectively, 4.88 ± 1.55 vs 7.60±1.91, 9.23 ± 2.66 vs 13.18 ± 2.72, 39.28 ± 20.35 vs 54.64 ± 23.34, all P < 0.01), while HOMA-IR reduced (4.41 ± 1.58 vs 3.52 ± 1.44, P < 0.05). But in IGla group only HOMA-IR was reduced (4.92 ± 1.84 vs 4.57 ± 1.80, P < 0.05). The index of ΔI30/ΔG30, AUCCP180 and Matsuda index in LIRA group are higher than those of indexes in IGla group(respectively, 7.60 ± 1.91 vs 4.18 ± 1.00, 13.18 ± 2.72 vs 10.53 ± 2.68,54.64 ± 23.34 vs 41.65 ± 17.84, all P < 0.05), while HOMA-IR is lower (3.52 ± 1.44 vs 4.57 ± 1.80, P< 0.05). (4) The rate of HbA1c ≤ 6.5% and the dosages of oral anti-diabetic drugs in LIRA group were significantly better than that in IGla group. (5) No significant differences were observed in hypoglycemic episodes and adverse events between two groups. CONCLUSION: It seems that liraglutide is superior to insulin glargine in newly diagnosed T2DM patients with HbA1c > 9% in improving beta-cell function, insulin sensitivity and glucose homeostasis.

[Efficacy and safety of alogliptin in treatment of type 2 diabetes mellitus: a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial in mainland China].

OBJECTIVE: To evaluate the efficacy and safety of alogliptin in Chinese patients with type 2 diabetes (T2DM). METHODS: This was a multicenter, randomized, double-blind, placebo-controlled phase III trial. A total of 491 subjects with T2DM were randomized in a 1:1 ratio to receive alogliptin (25 mg once daily) or placebo for 16 weeks. Among them, 181 were in the monotherapy group (group A), 186 were in the add-on to metformin group (group B), and 124 were in the add-on to pioglitazone group (group C). RESULTS: After 16 weeks of therapy, glycosylated hemoglobin A1c (HbA1c) levels decreased in both alogliptin and placebo groups. The mean changes in HbA1c for alogliptin and placebo were 1.00% and 0.43% (P<0.001), 0.91% and 0.23% (P<0.001), and 0.76% and 0.25% (P<0.001) in group A, B and C, respectively. Compared with placebo, alogliptin treatment led to a greater decrease in fasting plasma glucose (FPG) and a higher percentage of subjects who achieved HbA1c targets of ≤ 6.5% and ≤ 7.0%. The percentage of subjects who experienced all adverse events including hypoglycemia with alogliptin were comparable to those with placebo. CONCLUSIONS: Alogliptin 25 mg once daily reduced HbA1c and FPG, and increased a greater proportion of subjects achieving HbA1c goals of ≤6.5% and ≤7.0% compared with placebo when used as a monotherapy, add-on to metformin, or add-on to pioglitazone. The hypoglycemia rates and safety profiles with alogliptin were similar to those with placebo.

[The design and baseline characteristics of a phase III study to evaluate the efficacy and safety of alogliptin versus placebo in type 2 diabetes mellitus in Mainland China].

OBJECTIVE: To assess the design and the Mainland China subgroup baseline characteristics of the study to evaluate the efficacy and safety of alogliptin versus placebo in subjects with type 2 diabetes (T2DM) as monotherapy, add-on to metformin or add-on to pioglitazone. METHODS: This was a multi-center, randomized, double-blind, placebo-controlled, 16-week study comparing alogliptin (ALO, 25 mg, 1/d) versus placebo (PLA) as monotherapy (A), add-on to metformin (B) or add-on to pioglitazone ± metformin (C). The T2DM subjects with glycosylated hemoglobin A1c(HbA1c) between 7% and 10% and aged between 18 years and 75 years were enrolled and randomized to the alogliptin group and the placebo group in 1: 1 ratio with 16 weeks treatment. All patients were followed up every 4 weeks. The safety endpoints consisted of the incidence of hypoglycemia and other adverse events. RESULTS: A total of 491 patients were enrolled in the Mainland China subgroup of the study (181 in group A, 186 in group B and 124 in group C). In each treatment group, the baseline characteristics including age, gender, body mass index, diabetes duration, HbA1c, fasting plasma glucose, body weight, daily dosage of metformin and daily dosage of pioglitazone were all well balanced. CONCLUSION: The demographic data, medical history, glycemic profile and treatment regimen at baseline in Mainland China subgroup are well balanced. The result of this study will provide the clinical evidence for the use of alogliptin in Chinese T2DM patients.

[Effects of quercetin on nuclear factor-κB p65 expression in renal ubiquitin-proteasome system of diabetic rats].

OBJECTIVE: To investigate the protective effect of quercetin on diabetic nephropathy and to explore its possible mechanism. METHODS: Type 2 diabetes mellitus rat model was established by feeding high-carbohydrate-fat diet and injecting with streptozotocin. At 72 hour after injection, blood samples were collected from the tail veins of all rats. Those rats with blood glucose level ≥ 16.7 mmol/L were considered as the diabetes model been successfully established. The model rats were randomly divided into type 2 diabetic group (group DM, n = 9) and quercetin group (group QUE, n = 9). Other rats were used as normal controls (group NC, n = 8). All rats were performed by intragastric administration for 8 weeks. At the end of experiment, the rats were sacrificed and fasting plasma glucose (FPG), fasting insulin(FIns), serum creatinine (SCr), blood urea nitrogen (BUN), TG, TC, LDL-C, 24 h urine protein (24 h UP), and kidney index (KI) were evaluated. Pathological changes of kidney were observed by periodic acid-silver methenamine (PASM). The expressions of ubiquitin and NF-κB p65 on glomeruli were examined by immunohistochemical method, and its association with the incidence of proteinuria was analyzed. RESULTS: In groups DM and QUE, the level of FPG [(25.45 ± 1.23) mmol/L and (19.99 ± 1.20) mmol/L], FIns [(25.67 ± 2.58) mU/L and (19.29 ± 1.80) mU/L], SCr [(44.00 ± 2.53) µmol/L and (34.43 ± 2.23) µmol/L], BUN[(11.60 ± 0.39) mmol/L and (8.20 ± 0.37) mmol/L], TG[(3.32 ± 0.22)mmol/L and (2.43 ± 0.25) mmol/L], TC [(2.95 ± 0.21) mmol/L and (2.24 ± 0.17) mmol/L], LDL-C [(2.03 ± 0.22) mmol/L and (1.49 ± 0.13) mmol/L], 24 h UP[(46.67 ± 2.50) mg/24 h and (25.57 ± 2.82) mg/24 h] and KI [(9.76 ± 0.30)×10³ and (8.44 ± 0.26)×10³] were significantly increased than the indexes of group NC [(6.56 ± 0.41) mmol/L, (12.63 ± 1.41) mU/L, (22.88 ± 2.36) µmol/L, (5.45 ± 0.51) mmol/L, (1.64 ± 0.11) mmol/L, (1.33 ± 0.17) mmol/L, (0.46 ± 0.05) mmol/L, (12.38 ± 1.19)/24 h and (6.78 ± 0.12)×10³]. Moreover, the above indexes in group QUE were obviously lower than group DM. There was evidence of pathological changes associated with diabetes, such as focal and segmental sclerosis and thickened basement and mesangial expansion. The expressions of ubiquitin and NF-κB p65 in renal tissues of group DM increased significantly (P < 0.01). The expression of ubiquitin and NF-κB p65 were positively related with the level of 24 h UP (r = 0.893, 0.879, P < 0.01). Compared with group DM, all above indexes in group QUE were markedly alleviated (P < 0.01). The expression of ubiquitin and NF-κB p65 was reduced but didn't reach level in group NC (P < 0.01). CONCLUSION: The increased expression of NF-κB induced by ubiquitin-proteasome system may participate in the pathogenesis of proteinuria in diabetic nephropathy. Quercetin has renal protective effects partly through reducing NF-κB p65 expression.

Glucagon-like peptide-1 receptor agonist liraglutide therapy for psoriasis patients with type 2 diabetes: a randomized-controlled trial.

OBJECTIVE: There were some clinical studies on GLP-1R agonist liraglutide therapy for psoriasis patients with type 2 diabetes, but there is a lack of randomized controlled trials and the mechanism of which remains unclear. METHOD: A total of 25 psoriasis patients with type 2 diabetes were randomized 1: 1 divided into the control group (n = 13) or liraglutide group (n = 12) for 12 weeks. We determined the PASI, the DLQI, histopathology of psoriasis skin, and the expression of IL-17, IL-23, and TNF-α in the psoriasis skin. RESULTS: After 12 weeks of treatment, the mean DLQI of the treatment group decreased from 22.00 ± 5.85 to 3.82 ± 3.60 (p < .05). Compared to week 12, the change in the baseline value of PASI and DLQI in the treatment group showed a significant difference compared with the control group (p < .05). The pathological changes of psoriasis skin and the expression of IL-17, IL-23, TNF-α in the psoriasis skin were improved in the treatment group. No serious adverse events occurred. CONCLUSION: The skin lesions in psoriasis patients with type 2 diabetes were significantly improved after treatment with liraglutide, which may be related to the inhibition of the expression of inflammatory factors such as IL-23, IL-17, and TNF-α.

Risk of Death and Heart Failure among Patients with Type 2 Diabetes Treated by Metformin and Nonmetformin Monotherapy: A Real-World Study.

BACKGROUND: To assess the association of metformin monotherapy with the risk of all-cause deaths and cardiovascular deaths and events in type 2 diabetes patients in real clinical practice. METHODS: This retrospective, observational study comprised patients with type 2 diabetes initially treated with metformin or nonmetformin monotherapy over 2011-2016. Data were extracted from the National Healthcare Big Data database in Fuzhou, China. Propensity score matching (PSM) was performed, matching each patient on metformin to one on nonmetformin in terms of a set of covariates. The primary endpoint was all-cause death, and secondary endpoints were cardiovascular death, heart failure, and heart failure hospitalization. Covariate-adjusted associations of metformin use with all the endpoints were assessed by Cox proportional hazards models. RESULTS: Among 24,099 patients, 5491 were initially treated with metformin and 18,608 with nonmetformin. PSM yielded 5482 patients in each cohort. During a median follow-up of 2.02 years, we observed 110 and 211 deaths in the metformin and nonmetformin groups, respectively. Metformin was significantly associated with reduced risk of all-cause death (adjusted hazard ratio (aHR) 0.52, 95% confidence interval (CI) 0.39-0.69), cardiovascular death (aHR 0.63, 95% CI 0.43-0.91), and heart failure (aHR 0.61, 95% CI 0.52-0.73), whereas the reduced risk in heart failure hospitalization was not statistically significant (aHR 0.70, 95% CI 0.47-1.02). CONCLUSIONS: In this analysis of electronic health record data from a large database in China, metformin as first-line monotherapy greatly reduced the risk of all-cause death, cardiovascular death, and heart failure in diabetes patients as compared with nonmetformin medications.

Liraglutide improved inflammation via mediating IL-23/Th-17 pathway in obese diabetic mice with psoriasiform skin.

OBJECTIVES: The purpose of this study was to investigate the effect of liraglutide on obesity diabetic mice with psoriasiform skin inflammation. METHODS: Wild-type mice and db/db mice were randomly divided into five groups (n = 6): including the control group which received Vaseline, the imiquimod (IMQ)-induction group and the liraglutide-treatment group. The advanced treatment with liraglutide (0.3 mg/kg/d) for 4 weeks before IMQ induced psoriatic skin inflammation in the db/db + IMQ + Lira group. Basic parameters of diabetes, PASI, histopathology of skin, the expression of IL-17A, IL-23, IL-22, and TNF-α in the skin of back were measured. RESULTS: After IMQ induction, the psoriatic skin inflammation and pathological changes in the db/db + IMQ group were more serious than those in the WT + IMQ group. The glucose metabolism and insulin resistance of in the db/db + IMQ + Lira group were significantly improved, Psoriasis Area and Severity Index (PASI) was significantly reduced, and the protein and mRNA expressions of IL-23, IL-17, IL-22, and TNF-α in the back skin tissues were decreased. CONCLUSIONS: Liraglutide can improve psoriasis skin lesions of obese diabetic mice, and the mechanism may be related to the inhibition of the expression of IL-23, IL-17, IL-22, and TNF-α through the IL-23/Th-17 pathway.

Liraglutide in combination with human umbilical cord mesenchymal stem cell could improve liver lesions by modulating TLR4/NF-kB inflammatory pathway and oxidative stress in T2DM/NAFLD rats.

Studies have shown that liraglutide, or human umbilical cord mesenchymal stem cell (hUC-MSCs) can improve non-alcoholic fatty liver disease (NAFLD). However there have been no studies on the combination of the two used to treat NAFLD. This study aimed to explore the therapeutic effects of combination of liraglutide and hUC-MSCs on liver injury in rats with type 2 diabetes mellitus (T2DM) and NAFLD, and further investigate their mechanisms. Sprague Dawley rats fed by a high fat and high sucrose diet were randomly divided into 5 groups, including NC group, T2DM/NAFLD group, liraglutide group (treated with liraglutide, 200 µg/kg, twice daily for 8 weeks), hUC-MSCs group (treated with hUC-MSCs at the first and fifth weeks), liraglutid＋hUC-MSCs group (treated with liraglutide and hUC-MSCs). Liver tissue was procured for histological examination, real-time qRT-PCR and Western blot analysis. After treatment, liraglutide and hUC-MSCs reduced serum ALT and AST levels, alleviate liver inflammation and improved liver histopathology. The expressions of inflammatory cytokines, TLR4 and NF-κB in serum and liver were significantly inhibited, particularly in the combination treatment group. Eight weeks after liraglutide or hUC-MSCs administration, FBG, HbA1c, HOMA-IR, ALT, AST, Liver wet eight and hepatic TLR4, NF-κB, IL-6, TNF-α, 8-OHdG mRNA and proteins were significantly decreased, and the levels of SOD expression were significantly increased in three treatment groups compared with T2DM/NAFLD group. This study suggests that liraglutide in combination with hUC-MSCs could significantly improve glycolipid metabolism, insulin resistance and liver injury in T2DM/NAFLD rats. Its mechanism may be related to the down-regulation of the TLR4/NF-κB inflammatory pathway and improvement in oxidative stress.

Liraglutide or insulin glargine treatments improves hepatic fat in obese patients with type 2 diabetes and nonalcoholic fatty liver disease in twenty-six weeks: A randomized placebo-controlled trial.

BACKGROUND: Type 2 diabetes mellitus is closely related to nonalcoholic fatty liver disease(NAFLD). More and more attention has been paid to the efficacy of liraglutide in the treatment of NAFLD, but the clinical evidence is still insufficient. OBJECTIVE: The purpose of this study was to use proton magnetic resonance spectroscopy (H-MRS) assessment of metformin alone poor blood glucose control of obese patients type 2 diabetes with NAFLD, added with insulin glargine, liraglutide or placebo effect in improving the fatty liver. METHODS: This is a 26-week, single-center, prospective, randomized placebo-controlled study. From September 2016 to July 2018, 128 patients with type 2 diabetes and NAFLD were enrolled in the China joint logistics team 900 hospital. The primary endpoints were the changes in intrahepatic content of lipid (IHCL), abdominal adiposity [subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)], from baseline to week 26 (end of treatment) and the changes in liraglutide group or insulin glargine group versus change in placebo group. Secondary endpoints included the changes in liver function (AST and ALT), glycemia (HbA1c and FPG), body weight, and BMI. RESULTS: A total of 96 patients with type 2 diabetes and NAFLD under inadequate glycemic control by metformin were randomized (1:1:1) to receive add-on insulin glargine, liraglutide, or placebo. After 26 weeks of treatment, compared to the placebo group, in the liraglutide and insulin glargine groups, IHCL significantly decreased from baseline to week 26 (liraglutide 26.4% ± 3.2% to 20.6% ± 3.9%, P < 0.05; insulin glargine 25.0% ± 4.3% to 22.6% ± 5.8%, P > 0.05). SAT and VAT decreased significantly in the liraglutide group and in the insulin glargine group (P < 0.05). ΔSAT and ΔVAT were greater with liraglutide than insulin glargine, they were significantly different between the two groups (ΔSAT, -36 vs. - 24.5, P < 0.05; and ΔVAT, -47 vs. - 16.6, P > 0.05). In the liraglutide group, AST, ALT, and HOMA-IR decreased significantly from baseline. There was no significant difference in glucose-lowering among the three groups. During the treatment, the safety of the three groups performed well. CONCLUSION: Compared with placebo, treatment with liraglutide plus an adequate dose of metformin (2000 g/ day) for 26 weeks is more effective in reducing IHCL, SAT and VAT in patients with type 2 diabetes and NAFLD. And it has additional advantages in weight loss, waist circumference reduction and liver function improvement.

Insulin delivery with a needle-free insulin injector versus a conventional insulin pen in Chinese patients with type 2 diabetes mellitus: A 16-week, multicenter, randomized clinical trial (the FREE study).

BACKGROUND: Insulin therapy is poorly accepted by patients with type 2 diabetes mellitus (T2DM). A needle-free insulin injector has been developed for patients who fear injections or are reluctant to initiate insulin therapy when it is clearly indicated. The objective of this trial was to evaluate the glucose-lowering effect, tolerability, patient satisfaction and compliance with insulin treatment via a needle-free insulin injector (NFII) compared with insulin treatment via a conventional insulin pen (CIP) in patients with T2DM. METHODS: A total of 427 patients with T2DM were enrolled in a prospective, multicenter, randomized, open-label study, and were randomly assigned 1:1 to receive 16 weeks' treatment with basal insulin or premixed insulin administered either by a NFII or CIP. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03243903). FINDINGS: In the 412 patients who completed the study, the adjusted mean reduction of HbA1c from baseline at week 16 in the NFII group was 0.55% (95% CI -0.71, -0.39), which was non-inferior and statistically superior to the HbA1c reduction in the CIP group (0.26%, 95% CI -0.42, -0.11). Patients in the NFII group showed significantly higher treatment satisfaction scores than those in the CIP group (mean scores, 8.17 ± 1.78 vs. 7.21 ± 2.22, respectively; p<0.0001). The occurrence of hypoglycemia was similar in the two groups, and the NFII group showed reduced incidences of skin scratches, indurations and lower VAS pain scores. INTERPRETATION: Insulin therapy through needle-free injector showed a non-inferior glycemic-lowering effect and a significantly enhanced level of patient satisfaction with insulin treatment compared with conventional insulin therapy through needle injections. In addition, the needle-free injector also had a better safety profile. FUNDING: This study were funded by Beijing QS Medical Technology Co., Ltd, as well as The Major Chronic Non-communicable Disease Prevention and Control Research.

Efficacy and safety of DBPR108 monotherapy in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled, phase II clinical trial.

Objective: DBPR108, a novel dipeptidyl-peptidase-4 inhibitor, has shown great antihyperglycemic effect in animal models. This study was to evaluate the efficacy and safety of DBPR108 monotherapy in type 2 diabetes mellitus (T2DM).Methods: This was a 12-week, double-blind, placebo-controlled phase II clinical trial. The newly diagnosed or inadequately controlled untreated T2DM patients were randomized to receive 50, 100, 200 mg DBPR108 or placebo in a ratio of 1:1:1:1. The primary efficacy outcome was HbA1c change from baseline to week 12. Relevant secondary efficacy parameters and safety were assessed. The clinical trial registration is NCT04124484.Results: Overall, 271 of the 276 randomized patients, who received 50 mg (n = 68), 100 mg (n = 67), 200 mg (n = 69) DBPR108 or placebo (n = 67), were included in full analysis set. At week 12, HbA1c change from baseline was -0.04 ± 0.77 in placebo group, -0.51 ± 0.71, -0.75 ± 0.73, and -0.57 ± 0.78 (%, p < .001 vs. placebo) in 50, 100, and 200 mg DBPR108 groups, respectively. Since week 4, DBPR108 monotherapy resulted in significant improvements in secondary efficacy parameters. At end of 12-week treatment, the goal of HbA1c ≤7% was achieved in 29.85, 58.82, 55.22, and 47.83% of the patients in placebo, 50, 100, and 200 mg DBPR108 groups, respectively. The incidence of adverse events did not show significant difference between DBPR108 and placebo except mild hypoglycemia in DBPR108 200 mg group.Conclusions: The study results support DBPR108 100 mg once daily as the primary dosing regimen for T2DM patients in phase III development program.

Treatment with liraglutide, a glucagon-like peptide-1 analogue, improves effectively the skin lesions of psoriasis patients with type 2 diabetes: A prospective cohort study.

BACKGROUND: It has been reported that GLP-1 analogue can improve the skin lesions of psoriasis. However further research is needed to confirm that finding. OBJECTIVE: The study can provide further data regarding the efficacy and safety of GLP-1 analogue liraglutide in the treatment of psoriasis patients with type 2 diabetes. METHODS: We recruit 7 psoriasis patients with type 2 diabetes, and use hypodermic injection with liraglutide1.8 mg. In 12 weeks of treatment, we estimate the difference of before and after respectively, likeBMI, waist circumference, fasting blood glucose, fasting C-peptide, HbA1c, blood lipid levels, CRP, PASI, DLQI, skin tissue and pathological analysis of psoriasis. RESULTS: After 12 weeks of treatment, the mean value of PASI decreased from 15.7 ±â€¯11.8 to 2.2 ±â€¯3.0 (P = 0.03), while the DLQI decreased from 21.8 ±â€¯6 to 4.1 ±â€¯3.9 (P = 0.001). HbA1c was significantly improved after 12 weeks of treatment, decreased to 6.4 ±â€¯0.8% (P = 0.04), the BMI decreased to 21 ±â€¯3 kg m-2 (P < 0.01), and the waist circumference was also significantly improved to 83 ±â€¯1 cm (P < 0.05). And 12 weeks after, the fasting C-peptide levels increased to 1.9 ±â€¯0.5 ng/ml (P = 0.006), HOMA - IR fell to 1.6 ±â€¯0.6 (P = 0.03). Histological analysis showed a reduction in epidermal thickness after treatment. The mean PASI decreased from 15.7 (1.5-31.3) to 2.0 (0.3-8.7) (P = 0.03), the DLQI decreased from 22 (8-27) to 4 (0-10) (P = 0.001). CONCLUSION: GLP-1 analogueliraglutide can improve the skin lesions of psoriasis patients with type 2 diabetes effectively, especially for extremely severe psoriasis patients. Its therapeutic effect may be related to anti-inflammatory, hypoglycemic and reducing weight.