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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 ty...
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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 ).
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Background. Patients with psoriasis have an increased risk of type 2 diabetes. The gastrointestinal system plays a major role in normal glucose metabolism, and in healthy individuals, postprandial insulin secretion is largely medi...
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Background. Patients with psoriasis have an increased risk of type 2 diabetes. The gastrointestinal system plays a major role in normal glucose metabolism, and in healthy individuals, postprandial insulin secretion is largely mediated by the gut incretin hormones. This potentiation is termed the incretin effect and is reduced in type 2 diabetes. The impact of psoriasis on gastrointestinal factors involved in glucose metabolism has not previously been examined.
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Currently the prevalence of obesity and diabetes is increasing throughout the world. The unsatisfactory long-term results observed in the treatment of both are due to their complex pathophysiologies and the difficulties related to...
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Currently the prevalence of obesity and diabetes is increasing throughout the world. The unsatisfactory long-term results observed in the treatment of both are due to their complex pathophysiologies and the difficulties related to maintaining lifestyle changes. From the knowledge of the incretin effect and its alteration in patients with type 2 diabetes mellitus, GLP-1 receptor agonists arise, molecules with high structural homology with native GLP-1. Scientific evidence supports its use for the long-term treatment of diabetes, especially in the presence of associated cardiovascular and/or renal failure. In 2009, the use of liraglutide for patients with diabetes was approved in Europe, and in 2014 it was signed for the first time in the United States to treat obesity, since it was observed that the use of these drugs causes significant weight loss.
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Although Roux-en-Y Gastric Bypass (RYGB) remains the most effective treatment for obesity and type 2 diabetes (T2D), many patients fail to achieve remission, or relapse. Increasing intestinal limb lengths of RYGB may improve outco...
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Although Roux-en-Y Gastric Bypass (RYGB) remains the most effective treatment for obesity and type 2 diabetes (T2D), many patients fail to achieve remission, or relapse. Increasing intestinal limb lengths of RYGB may improve outcomes, but the mechanistic basis for this remains unclear. We hypothesize biliopancreatic (BP) limb length modulates the antidiabetic effect of RYGB. Rats underwent RYGB with a 20-cm (RYGB-20cm) or 40-cm (RYGB-40cm) BP limb and were compared with control animals. After 2 and 4 wk, portal and systemic blood was sampled during intestinal glucose infusion. Portosystemic gradient was used to calculate intestinal glucose utilization (G_(util)), absorption (G_(absmp)), and hormone secretion. Intestinal morphology and gene expression were assessed. At 2 wk, G_(absorp) progressively decreased with increasing BP limb length; this pattern persisted at 4 wk. G_(util) increased ≈70% in both RYGB-20cm and -40cm groups at 2 wk. At 4 wk, G_(util) progressively increased with limb length. Furthermore, Roux limb weight, and expression of hexokinase and preproglucagon, exhibited a similar progressive increase. At 4 wk, glucagon-like peptide-1 and -2 levels were higher after RYGB-40cm, with associated increased secretion. We conclude that BP limb length modulates multiple antidiabetic mechanisms, analogous to the dose-response relationship of a drug. Early postoperatively, a longer BP limb reduces G_(absorp). Later, G_(util), Roux limb hypertrophy, hormone secretion, and hormone levels are increased with longer BP limb. Sustained high incretin levels may prevent weight regain and T2D relapse. These data provide the basis for customizing BP limb length according to patient characteristics and desired metabolic effect.
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The role of incretins in glucose homeostasis is well known. Yet, in recent years, the sustained weight loss and rapid glycemic control following bariatric surgery has challenged our understanding of the intestinal-pancreatic inter...
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The role of incretins in glucose homeostasis is well known. Yet, in recent years, the sustained weight loss and rapid glycemic control following bariatric surgery has challenged our understanding of the intestinal-pancreatic interaction. This in turn led to the introduction of metabolic surgery, an innovative medical discipline in which a surgical manipulation of the gastrointestinal tract (e.g., through a Roux-en-Y gastric bypass, RYGB, or Bilio-Pancreatic-Diversion, BPD) yields a sustained remission of diabetes mellitus. The pathophysiological background of this metabolic effect is, amongst other things, based on the anti-incretin theory. This theory postulates that in addition to the well-known incretin effect, nutrient passage through the GI-tract could also activate negative feedback mechanisms (anti-incretins) to balance the effects of incretins and other postprandial glucose-lowering mechanisms (i.e., suppression of ghrelin, glucagon, and hepatic glucose production via activation of nutrient sensing). This in turn prevents postprandial hyperinsulinemic hypoglycemia. The bypass of the duodenum, the entire jejunum and the first portion of the ileum by BPD induce normalization of peripheral insulin sensitivity, while the bypass of a shorter intestinal tract by RYGB mainly improves the hepatic insulin sensitivity. In addition, RYGB greatly increases insulin secretion. Therefore, metabolic surgery highlights the important role of the small intestine in glucose homeostasis, while until few years ago, it was only the pancreas and the liver that were thought to represent the regulatory organs for glucose disposal.
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Aims: To review the evolution and advancement of GLP-1 receptor agonist (GLP-1RA) therapy, through the lens of randomised controlled trials, from differentiating characteristics, efficacy, safety, tolerability, and cardiovascular ...
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Aims: To review the evolution and advancement of GLP-1 receptor agonist (GLP-1RA) therapy, through the lens of randomised controlled trials, from differentiating characteristics, efficacy, safety, tolerability, and cardiovascular outcomes, to evidence gaps and next steps.
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Abstract Aim Liraglutide treatment is associated with gallbladder‐related disorders and has been shown to delay postprandial gallbladder refilling. The gut hormones cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and g...
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Abstract Aim Liraglutide treatment is associated with gallbladder‐related disorders and has been shown to delay postprandial gallbladder refilling. The gut hormones cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and glucagon‐like peptide 2 (GLP‐2), are known to regulate gallbladder motility and may be implicated in gallbladder‐related disorders associated with liraglutide treatment. Materials and Methods In a double‐blind, 12‐week trial, 52 participants [50% male, age 47.6?±?10.0?years, body mass index 32.6?±?3.4?kg/m2 (mean?±?standard deviation)] with obesity were randomized 1:1 to once‐daily subcutaneous liraglutide (escalated from 0.6?mg to 3.0?mg once‐daily) or placebo. During liquid meal tests performed at baseline, after the first dose and following 12?weeks of treatment, we evaluated postprandial gallbladder dynamics and plasma responses of CCK, FGF19 and GLP‐2. Results Liraglutide reduced postprandial FGF19 after the first dose [area under the curve (AUC)0‐240 min 24.8 vs. 48.0?min?×?ng/ml, treatment ratio (TR) (95% confidence interval) 0.52 (0.39; 0.69)] and following 12?weeks of treatment [AUC0‐240 min 33.7 vs. 48.5?ng/ml?×?min, TR 0.69 (0.52; 0.93)]. Liraglutide also reduced postprandial GLP‐2 responses (AUC0‐240 min 3650 vs. 4894?min?×?pmol/L, TR 0.75 (0.62; 0.90)] following the first dose as well as after 12?weeks [AUC0‐240 min 3760 vs. 4882?min?×?pmol/L, TR 0.77 (0.60; 0.99)]. Liraglutide increased postprandial responses of CCK after the first dose [AUC0‐240 min 762 vs. 670?min?×?pmol/L; TR 1.14 (0.97; 1.33)] and following 12?weeks of treatment [AUC0‐240 min 873 vs. 628?min?×?pmol/L; TR 1.39 (1.12; 1.73)]. Conclusion Compared with placebo, treatment with liraglutide decreased postprandial FGF19 and GLP‐2 concentrations and increased postprandial CCK concentrations, which may explain the delayed postprandial gallbladder refilling observed in individuals with obesity treated with liraglutide.
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Aims/Introduction: Type 2 diabetes mellitus is a progressive disease that frequently requires patients to use more than one oral antihyperglycemic agent to achieve adequate glycemic control. The present multicenter, randomized stu...
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Aims/Introduction: Type 2 diabetes mellitus is a progressive disease that frequently requires patients to use more than one oral antihyperglycemic agent to achieve adequate glycemic control. The present multicenter, randomized study assessed the efficacy and safety of the addition of sitagliptin to ongoing voglibose monotherapy (0.2-0.3 mg three times daily) in Japanese patients with type 2 diabetes mellitus who had inadequate glycemic control (glycated hemoglobin ≥6.9% and <10.5%). Materials and Methods: The present study had an initial 12-week, double-blind treatment period in which patients were randomized (1:1) to sitagliptin 50 mg/day (n = 70) or placebo (n = 63), followed by a 40-week, open-label treatment period during which all patients received sitagliptin 50 mg/day, that could have been increased to 100 mg/day for patients meeting predefined glycemic criteria. Results: After 12 weeks, treatment with sitagliptin resulted in placebo-subtracted mean changes from baseline in glycated hemoglobin (the primary end-point), fasting plasma glucose and 2-h postmeal glucose of -0.9%, -22.5 mg/dL and -51.3 mg/dL, respectively (all, P < 0.001). During the double-blind period, adverse experiences were reported with similar frequency in both treatment groups, and the occurrences of hypoglycemia and gastrointestinal adverse experiences were low. In the open-label period, sustained improvements in glycemic parameters were observed with sitagliptin treatment, and sitagliptin was generally well tolerated. Conclusions: Sitagliptin added on to ongoing voglibose monotherapy provided significant improvements in glycemic parameters and was well tolerated in Japanese patients with type 2 diabetes mellitus who had inadequate glycemic control. This trial was registered with ClinicalTrails.gov (no. NCT00837577).
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Since diabetes mellitus (DM) is the most common cause of heart failure (HF), it is critically important to clarify whether incretin hormones including glucagon-like peptide-1 (GLP-1), which play an important role in blood glucose ...
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Since diabetes mellitus (DM) is the most common cause of heart failure (HF), it is critically important to clarify whether incretin hormones including glucagon-like peptide-1 (GLP-1), which play an important role in blood glucose control, mediate cardioprotection. There are many lines of basic research evidence indicating that GLP-1 improves the pathophysiology of BF: In murine and canine HF models, either GLP-1 analogues or DPP-IV inhibitors improved cardiac functions. The first question that arises is how either GLP-1 analogues or DPP-IV inhibitors mediate cardioprotection. Cardiovascular diseases are tightly linked to impaired glucose tolerance (IGT): IGT is not only one of the causes of cardiovascular events but also the result of BE Indeed, the treatment of IGT improved HF, showing that one of the mechanisms attributable to DPP-W inhibitors is related to the improvement of IGT. Intriguingly, either DPP-IV inhibitors or GLP-1 analogues mediate cardioprotection even without IGT, suggesting two possible explanations: One is that GLP-1 analogues directly activate the prosurvival kinases, such as Ala and Erk1/2, and another is that DPP-IV inhibition increases cardioprotective peptides such as BNP and SDF-1 alpha. The next question is whether cardioprotection is translated to clinical medicine. Small scale clinical trials proved their cardioprotective effects; however, several large scale clinical trials have not proved the beneficial effects of DPP-IV inhibitors. Taken together, GLP-1 analogues or DPP-IV inhibitors can mediate cardioprotection, however, what needs to be clarified is who mainly receives their benefits among the patients with cardiovascular diseases and/or DM.
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