Showing papers by "Filip K. Knop published in 2012"
TL;DR: Evidence is provided that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.
Abstract: Objective To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus. Design Systematic review with meta-analyses. Data sources Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011). Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin. Data extraction Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors. Results 25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference −2.9 kg, 95% confidence interval –3.6 to –2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (–3.2 kg, –4.3 to –2.1; three trials) as well as patients with diabetes (–2.8 kg, –3.4 to –2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia. Conclusions The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.
740 citations
TL;DR: People with type 2 diabetes mellitus are characterized by reduced incretin effect and inappropriate glucagon levels, and α and β‐cell responses to oral glucose tolerance test and isoglycaemic intravenous glucose infusion in lean and obese persons with T2DM or normal glucose tolerance (NGT) are evaluated to elucidate the impact of obesity.
Abstract: Aims: People with type 2 diabetes mellitus (T2DM) are characterized by reduced incretin effect and inappropriate glucagon levels. We evaluated α and β-cell responses to oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion (IIGI) in lean and obese persons with T2DM or normal glucose tolerance (NGT) to elucidate the impact of obesity on the incretin effect and incretin hormone and glucagon responses.
Methods: Four hour 50-g OGTT and IIGI were performed in (i) Eight obese patients with T2DM [mean body mass index (BMI): 37 (range: 35–41) kg/m2]; (ii) Eight obese subjects with NGT [BMI: 33 (35–38) kg/m2]; (iii) Eight lean patients with T2DM [BMI: 24 (22–25) kg/m2]; and (iv) Eight lean healthy subjects [BMI: 23 (20–25) kg/m2].
Results: The incretin effect was significantly (p < 0.05) reduced in patients with T2DM {obese: 7 ± 7% [mean ± standard error of the mean (SEM)]; lean: 29 ± 8%; p = 0.06)} and was lower in obese subjects (41 ± 4%) than in lean subjects with NGT (53 ± 4%; p < 0.05). Obese subjects with NGT were also characterized by elevated fasting plasma glucagon levels, but the inappropriate glucagon responses to OGTT found in the T2DM patients were not evident in these subjects.
Conclusions: Our findings suggest that reduced incretin effect and fasting hyperglucagonaemia constitute very early steps in the pathophysiology of T2DM detectable even in obese people who despite their insulin-resistant state have NGT.
152 citations
TL;DR: This article critically evaluates the current evidence for a role of GLP‐1 in RYGB‐induced remission of T2DM and concludes that the former is likely to be a key mediator in the latter.
Abstract: Weight-reducing surgical procedures such as Roux-en-Y gastric bypass (RYGB) have proven efficient as means of decreasing excess body weight. Furthermore, some studies report that up to 80% of patients with type 2 diabetes mellitus (T2DM) undergoing RYGB experience complete remission of their T2DM. Interestingly, the majority of remissions occur almost immediately following the operation and long before significant weight loss has taken place. Following RYGB, dramatic increases in postprandial plasma concentrations of the incretin hormone glucagon-like peptide-1 (GLP-1) have been recorded, and the known antidiabetic effects of GLP-1 are thought to be key mediators in RYGB-induced remission of T2DM. However, the published studies on the impact of RYGB on GLP-1 secretion are few, small and often not controlled properly. Furthermore, mechanistic studies delineating the role of endogenous GLP-1 secretion in RYGB-induced remission of T2DM are lacking. This article critically evaluates the current evidence for a role of GLP-1 in RYGB-induced remission of T2DM.
49 citations
TL;DR: Data show that impairment of the insulinotropic effect of both GIP and GLP-1 can be induced in healthy male subjects without risk factors for type 2 diabetes, indicating that the reduced insulinotrop effect of the incretin hormones observed in type 1 diabetes most likely is a consequence of insulin resistance and glucose intolerance rather than a primary event causing the disease.
Abstract: Objective: The insulinotropic effect of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) is impaired in patients with type 2 diabetes. It remains unclear whether this impairment is a primary pathophysiological trait or a consequence of developing diabetes. Therefore, we aimed to investigate the insulinotropic effect of GIP and GLP-1 compared with placebo before and after 12 d of glucose homeostatic dysregulation in healthy subjects. Research Design and Methods: The insulinotropic effect was measured using hyperglycemic clamps and infusion of physiological doses of GIP, GLP-1, or saline in 10 healthy Caucasian males before and after intervention using a high-calorie diet, sedentary lifestyle, and administration of prednisolone (37.5 mg once daily) for 12 d. Results: The intervention resulted in increased insulin resistance according to the homeostatic model assessment (1.2 ± 0.2 vs. 2.6 ± 0.5, P = 0.01), and glucose tolerance deteriorated as ass...
41 citations
TL;DR: It is proposed that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain.
Abstract: Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia. Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes between schizophrenia and overweight patients. Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed. We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted.
28 citations
TL;DR: Patients with CP and secondary DM have elevated levels of YKL-40 and IL-6 compared to CP patients with NGT and healthy subjects, suggesting that YKl-40 is not a primary mediator of DM but a consequence of the diabetic state.
Abstract: OBJECTIVES Circulating levels of YKL-40 and interleukin 6 (IL-6) are elevated in patients with type 2 diabetes. We aimed to evaluate YKL-40 levels in patients with chronic pancreatitis (CP) with and without secondary diabetes mellitus (DM) to investigate whether elevated plasma YKL-40 could play a primary role in the pathogenesis of type 2 diabetes or rather represent a consequence of the diabetic state. METHODS Plasma levels of YKL-40 and IL-6 were measured during an oral glucose tolerance test in 8 patients with CP and secondary DM, 8 patients with CP and normal glucose tolerance (NGT), and 8 healthy control subjects (CTRLs). RESULTS Plasma YKL-40 and IL-6 were significantly higher in patients with CP and secondary DM (YKL-40, mean [95% confidence interval], 113 [60-215 ng/mL]; IL-6, 4.6 [2.3-9.1 pg/mL]) compared to patients with CP and NGT (YKL-40, 42 [28-63 ng/mL]; IL-6, 1.4 [0.8-2.4 pg/mL]) and healthy control subjects (YKL-40, 46 [31-69 ng/mL]; IL-6, 1.4 [0.8-2.4 pg/mL]). CONCLUSIONS Patients with CP and secondary DM have elevated levels of YKL-40 and IL-6 compared to CP patients with NGT and healthy subjects, suggesting that YKL-40 is not a primary mediator of DM but a consequence of the diabetic state.
16 citations
TL;DR: A considerable proportion of patients with T2DM treated with SU are not aware of the risks of hypoglycaemia and weight gain associated with the treatment, suggesting that these patients might be insufficiently informed about side effects.
Abstract: Background and aims:Hypoglycaemia and body weight gain are side effects of certain glucose-lowering drugs, e.g. sulphonylurea (SU) compounds. Type 2 diabetes mellitus (T2DM) is often treated with multiple oral antidiabetic drugs complicating patient insight into drug safety and side effects. We aimed to elucidate the extent of patient worry about hypoglycaemia and body weight gain contra their knowledge about these two phenomena being actual side effects of SU.Methods:We used an observational, cross-sectional approach and included 492 patients with T2DM: 331 (67%) on metformin alone (MET), 52 (11%) on SU in monotherapy (SU), and 109 (22%) on metformin in combination with SU (MET + SU). All participants filled in a questionnaire enquiring about the patient’s knowledge and worry about side effects such as hypoglycaemia and weight gain in addition to the importance of their treatment not eliciting these two side effects.Results:Nineteen (MET), 29 (SU) and 38% (MET + SU) of the patients in the three g...
15 citations
TL;DR: The present situation shows that, without a legal obligation to provide placebos to match their marketed drugs, the pharmaceutical industry has de-facto control over drug trials.
12 citations
TL;DR: A systematic review with meta-analysis of the glucose-lowering effect of BASs with the aim of evaluating their potential as glucose- Lowering agents in patients with type 2 diabetes mellitus.
Abstract: Introduction In addition to the lipid-lowering effect of bile acid sequestrants (BASs), they also lower blood glucose and, therefore, could be beneficial in the treatment of patients with type 2 diabetes mellitus (T2DM). Three oral BASs are approved by the US Food and Drug Administration (FDA) for the treatment of hypercholesterolaemia: colestipol, cholestyramine and colesevelam. The BAS colestimide/colestilan is used in Japan. Colesevelam was recently approved by the FDA for the treatment of T2DM. We plan to provide a systematic review with meta-analysis of the glucose-lowering effect of BASs with the aim to evaluate their potential as glucose-lowering agents in patients with T2DM. Methods and analysis In accordance with the preferred reporting items for systematic reviews and meta-analyses statement, a systematic review with meta-analysis of randomised clinical trials of BASs (vs placebo, oral antidiabetes drugs or insulin), reporting measures of glycaemic control in adult patients with T2DM, will be performed. Change in glycated haemoglobin constitutes the primary endpoint, and secondary endpoints include changes in fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, body weight and body mass index and adverse events. Electronic searches will be performed in The Cochrane Library, MEDLINE and EMBASE, along with manual searches in the reference lists of relevant papers. The analyses will be performed based on individual patient data and summarised data. The primary meta-analysis will be performed using random effects models owing to expected intertrial heterogeneity. Dichotomous data will be analysed using risk difference and continuous data using weighted mean differences, both with 95% CIs. Ethics and dissemination The study will evaluate the potential of BASs as glucose-lowering agents and possibly contribute to the clinical management of patients with T2DM. Results The study will be disseminated by peer-review publication and conference presentation. Protocol registration PROSPERO CRD42012002552.
9 citations
TL;DR: In vitro data suggest that glucose-dependent insulinotropic polypeptide (GIP) inhibits free fatty acid (FFA) release via direct insulin-independent effects and a clinical study in which 11 obese male subjects were studied during two 240-min intravenous infusions with GIP.
Abstract: Gogebakan et al. (1) suggest that glucose-dependent insulinotropic polypeptide (GIP) inhibits free fatty acid (FFA) release via direct insulin-independent effects. Their in vitro data are accompanied by a clinical study in which 11 obese male subjects were studied during two (blinded?) 240-min intravenous infusions with GIP (2 pmol/kg/min) and saline, respectively. Because insulin is a well-known suppressor of circulating FFAs, one of the challenges that Gogebakan et al. encounter is to differentiate between the effect of GIP per se and any indirect effects of GIP (in particular via insulin) as outlined by Asmar et al. (2,3). Gogebakan et al. state that the trial was performed under euglycemic and …
TL;DR: It is concluded that prednisolone had no detectable effect on the ffERG in healthy lean men in this study, and retinal function may be less sensitive to changes in glycemia in healthy subjects than in people with diabetes.
Abstract: This study examined electroretinographic function in healthy subjects before and after prednisolone intake. To separate the effect of prednisolone on the retina from the potentially confounding hyperglycemia-inducing effect of prednisolone, electroretinography was made while fasting and at a pre-specified level of clamped hyperglycemia. The study included 10 eyes in 10 healthy lean men aged 25 ± 3 years (mean ± SD). The subjects were examined before and after oral intake of prednisolone 37.5 mg/day for 9.1 ± 1.4 days. The diabetogenic potential of prednisolone was reinforced by the intake of a high-caloric diet and by the reduction of physical activity. Full-field electroretinography (ffERG) demonstrated no significant change (P 0.05). The stability of ffERG performance in the face of shifting glycemia levels, which differs from what has been found in diabetes, was not influenced by the mild diabetogenic effect of the intervention on insulin resistance (P = 0.011) and post-prandial glycemia (P = 0.023). We conclude that prednisolone had no detectable effect on the ffERG in healthy lean men in this study. Retinal function may be less sensitive to changes in glycemia in healthy subjects than in people with diabetes, a characteristic that was unchanged by a short course of prednisolone.
TL;DR: New evidence could aid clinicians in deciding between one of the most commonly used second-line agents, glimepiride, and the recently approved dipeptidyl peptidase 4 inhibitor linagliptin.
Abstract: Clinicians are responsible for selecting a suitable second-line treatment for patients with type 2 diabetes mellitus when metformin monotherapy fails. New evidence could aid clinicians in deciding between one of the most commonly used second-line agents, glimepiride, and the recently approved dipeptidyl peptidase 4 inhibitor linagliptin.
TL;DR: The authors speculate that the high-density lipoprotein cholesterol–augmenting effect of torcetrapib could have direct effects on insulin secretion and insulin sensitivity, or perhaps the drug could exhibit off-target effects unrelated to inhibition of CETP.
Abstract: To the Editor:
The recent post hoc analysis of the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial by Barter et al1 strongly suggests that the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib improves glycemic control. The authors speculate that the high-density lipoprotein cholesterol–augmenting effect of torcetrapib could have direct effects on insulin secretion and insulin sensitivity (despite the fact that the plasma concentration of high-density lipoprotein cholesterol did not correlate with glycemic improvements), or perhaps the drug could exhibit off-target effects unrelated to inhibition of CETP.1 Nevertheless, the answer to the key question of which mechanisms drive the surprising effect reported by …
TL;DR: It is found that glucagon-like peptide-1 receptor (GLP-1R) agonists suppress appetite and lead to clinically beneficial weight loss, improved glycaemic control (in patients with type 2 diabetes), and reduced blood pressure and cholesterol values over 20 weeks.
Abstract: We found that glucagon-like peptide-1 receptor (GLP-1R) agonists suppress appetite and lead to clinically beneficial weight loss, improved glycaemic control (in patients with type 2 diabetes), and reduced blood pressure and cholesterol values over 20 weeks1—clinically relevant treatment results.2 The effect is sustained for up to two years in most patients.3 Several large cardiovascular outcome trials, each of up …