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Aim: To perform a direct, double-blind, randomised, crossover comparison of subcutaneous and intravenous glucagon-like peptide-1 (GLP-1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP-1-based therapy., Materials and Methods: Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP-1 and intravenous saline, or intravenous GLP-1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg -1 ·min -1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg -1 ·min -1 for intravenous). Plasma glucose, total and intact GLP-1, insulin, C-peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM., Results: Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP-1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP-1 increased dose-dependently, but more with intravenous than subcutaneous for both total (∆ max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP-1 (∆ max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP-1 clearance was higher for subcutaneous than intravenous GLP-1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP-1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each)., Conclusions: Subcutaneous GLP-1 administration is much less efficient than intravenous GLP-1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The role of gut-brain axis functioning gains growing attention in research on the pathophysiology of major depressive disorders. Here, especially consequences of altered microbiota composition on tryptophan metabolism resulting in altered serotonergic neurotransmission in the central nervous system (CNS) have reached a central position. Previous research, however, mainly focused on either microbiota and peripheral serotonin levels or central serotonergic neurotransmission. The present study aimed to combine the analysis of microbiota composition and central serotonergic activity using a valid neurophysiological indicator. We recruited 19 adult patients with type 1 diabetes and depression (D + D; 7 males), 19 patients with type 1 diabetes (D-; 7 male), and 20 healthy participants (HC; 7 males). Next to the analysis of fecal microbiota regarding α- and β-diversity, the loudness dependence of auditory evoked potential (LDAEP) was investigated, a non-invasive measurement of central serotonergic activity. High α-diversity was associated with high LDAEP, i.e., low serotonergic activity, in patients with diabetes and additional depression. Furthermore, relative abundances of bacterial families belonging to Bacteroidetes, Proteobacteria and Firmicutes were shown to have an impact on central serotonergic activity. This finding was supported by a tendency indicating an association of central serotonergic activity with the Bacteroidetes-Firmicutes ratio in both patients' groups. Together, this data suggests that the guts' microbiota composition might play an important role in regulating the central serotonergic activity in the brain., (© 2023. The Author(s).)

Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials., (© 2023 John Wiley & Sons Ltd.)

Background: We previously published an algorithm predicting 24 h basal insulin infusion profiles in insulin pump-treated subjects with type 1 diabetes profiles from six subject characteristics. This algorithm was to be externally validated in an independent environment and patient population., Methods: Thirty-two patients with pump-treated type diabetes were switched to their individually algorithm-derived basal insulin infusion profile, and the appropriateness of fasting glycemic control was scrutinized by means of a supervised 24 h fast. Primary endpoint was appropriate fasting glycemic control according to pre-defined criteria in at least 80% of the cohort., Results: In 24 out of 32 patients switching to the algorithm-derived basal insulin infusion rate and undergoing a 24-h fasting period, appropriate glycemic control was achieved (=75%, lower than the pre-defined threshold of 80%), two patients discontinued the fast due to hyperglycemia, and six finished the fasting period, however, with inappropriate fasting glycemic control (entirely due to hyperglycemic episodes). There were no obvious differences in baseline characteristics between those with appropriate vs. inappropriate fasting glycemic control on the basal insulin infusion rate provided by the algorithm., Conclusion: In conclusion, when testing fasting glycemic control with an algorithm-derived individual basal insulin infusion profile during a 24 h fasting period in a cohort unrelated in terms of the hospital environment and catchment area, the success rate was lower than a pre-defined threshold for concluding utility of this algorithm. Therefore, applying this algorithm in order to initiate or optimize basal insulin infusion profiles in type 1 diabetes cannot be generally recommended., Competing Interests: MAN has been a member of advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co., Menarini/Berlin Chemie, Merck, Sharp & Dohme, Novo Nordisk, Pfizer, Regor, and ShouTi. He has received grant support from Eli Lilly & Co., Merck, Sharp & Dohme, and Novo Nordisk. He has also served on the speakers’ bureau of AstraZeneca, Boehringer Ingelheim, Centrix, Eli Lilly & Co., Menarini/Berlin Chemie, Medscape, Medical Learning Institute, Merck, Sharp & Dohme, and Novo Nordisk. JJM has received consulting and speaker honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Sharp & Dohme, Novo Nordisk, and Sanofi. He has received research support from Eli Lilly, Boehringer-Ingelheim, Merck, Sharp & Dohme, Novo Nordisk, Novartis, and Sanofi. MK-S, AML, and SW, have nothing to declare., (Thieme. All rights reserved.)

Aim: Glucagon-like peptide-1 receptor agonists improve glycaemic control: some are now available as oral and subcutaneous formulations, and some have indications for reducing cardiovascular risk. The expanded scope for these therapies warrants comprehensive safety evaluations. We report the safety/tolerability of subcutaneous and oral semaglutide from the SUSTAIN and PIONEER clinical trial programmes, respectively., Materials and Methods: Adverse events (AEs) from 16 randomized placebo- or active-controlled phase IIIa trials in patients with type 2 diabetes (n = 11 159) including once-weekly subcutaneous semaglutide (n = 3150; SUSTAIN trials) or once-daily oral semaglutide (n = 4116; PIONEER trials) were analysed. Data pools were analysed for each programme, with separate analyses of cardiovascular outcomes trials (CVOTs; n = 6480)., Results: In the phase IIIa pools, gastrointestinal disorders were reported in 41.9%/39.1% of patients with subcutaneous/oral semaglutide, respectively (most prevalent during initiation/escalation) versus 22.0%/24.8% with comparators. Rates of kidney disorders, acute pancreatitis, malignant neoplasms, hypoglycaemia, diabetic retinopathy, heart failure and other cardiovascular events were similar for semaglutide versus comparators. Cholelithiasis incidence was higher with subcutaneous and oral semaglutide versus placebo. Diabetic retinopathy incidence was higher with subcutaneous semaglutide versus placebo in SUSTAIN 6. Small pulse rate increases occurred with both formulations; there was no increased rate of arrhythmias. Fatal AE incidence was similar between semaglutide and comparators. Versus placebo, CVOTs showed a reduced risk of major adverse cardiovascular events with subcutaneous semaglutide and non-inferiority criteria were met with oral semaglutide., Conclusions: The most common AEs with semaglutide were gastrointestinal disorders, which decreased with continued therapy. These comprehensive safety/tolerability data may better inform patient selection and guidance in care., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: Gastrointestinal disorders, including constipation and fecal incontinence, are common in type 2 diabetes mellitus (T2DM) and may derive from diabetic autonomic neuropathy, severe intestinal bacterial overgrowth, or a dysfunctional anorectal sphincter. The present study aims to characterize the correlation between these conditions., Methods: Patients with T2DM, prediabetes, and normal glucose tolerance (NGT) were included. The anorectal function was assessed with high-resolution anorectal manometry. Patients were screened for autonomic neuropathy by measuring olfactory, sweat, and erectile dysfunction as well as heart rate variability. Constipation and fecal (in-)continence were evaluated using validated questionnaires. Breath tests were used to assess severe intestinal bacterial overgrowth., Results: We included 59 participants (32 (54.2%) with T2DM, 9 (15.3%) with prediabetes, and 18 (30.5%) NGT). The presence of autonomic neuropathy, severe bacterial overgrowth, and symptoms of constipation and incontinence were comparable. HbA 1c was correlated with an increased anorectal resting sphincter pressure ( r =0.31, P =0.019) and constipation symptoms ( r =0.30, P =0.031). In patients with a long-standing diagnosis of T2DM, significantly higher values for maximum anorectal resting pressure (Δ=+27.81±7.84 mmHg, P =0.0015) and baseline pressure (Δ=20.50±9.74 mmHg, P =0.046) were found compared with NGT, but not with prediabetes., Conclusions: Long-standing T2DM increases anorectal sphincter activity, and constipation symptoms are associated with higher HbA 1c levels. The lack of an association of symptoms with autonomic neuropathy suggests glucotoxicity as the primary mechanism., Competing Interests: JJM has received lecture honoraria and consulting fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme (MSD), Novo Nordisk, Novartis, and Sanofi; has received reimbursement of congress participation fees and travel expenses from MSD, Novo Nordisk, and Sanofi; and has initiated projects supported by Boehringer-Ingelheim, MSD, Novo Nordisk, and Sanofi.; DRQ was granted a research award sponsored by Sanofi.; GCB, BAM, TGKB, and NS have nothing to disclose., (Thieme. All rights reserved.)

In clinical practice, the distinction between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) can be challenging, leaving patients with "ambiguous" diabetes type. Insulin-treated patients (n=115) previously diagnosed with T2DM had to be re-classified based on clinical phenotype and laboratory results, and were operationally defined as having an ambiguous diabetes type. They were compared against patients with definite T1DM and T2DM regarding 12 clinical and laboratory features typically different between diabetes types. Characteristics of patients with ambiguous diabetes type, representing approximately 6% of all patients with T1DM or T2DM seen at our specialized clinic, fell in between those of patients with definite T1DM and T2DM, both regarding individual features and with respect to a novel classification based on multi-variable regression analysis (P<0.0001). In conclusion, a substantial proportion of diabetes patients in a tertiary care centre presented with an "ambiguous" diabetes type. Their clinical characteristics fall in between those of definite T1DM or T2DM patients.

Cardiovascular outcomes trials (CVOTs) with novel drugs to treat type 2 diabetes have uniformly chosen the composite "major adverse cardiovascular events (MACE)" as their primary endpoint, but they also report hazard ratios for individual cardiovascular outcomes (myocardial infarction, stroke, cardiovascular death, all-cause death, hospitalization for heart failure). We wanted to scrutinize the power to identify significant differences with respect to individual as compared to composite outcomes. We estimated post hoc the statistical power to detect significant differences of 10-25% for published studies, comparing the proportions of patients with an event (two-sided log-rank tests). For MACE, the power to detect a 15% difference ranged from 82.3 to 100.0% for larger trials, but was only 69.1 and 50.5 for smaller, preliminary trials (SUSTAIN-6 and PIONEER-6). For individual endpoints, the power, as a rule, was substantially lower. In conclusion, cardiovascular outcomes trials had appropriate power to detect significant reductions in hazard ratios with respect to the primary endpoint, but not for individual cardiovascular outcomes. This was particularly the case for small, preliminary studies. Our results call for caution when comparing results regarding individual endpoints between CVOTs, if the aim is to identify heterogeneity within or between medication classes., (© 2022. The Author(s).)

Introduction: Breath tests utilising 13 C-labelled substrates for the assessment of gastric emptying have been applied widely. Wagner-Nelson analysis is a pharmacokinetic model that can be utilised to generate a gastric emptying curve from the %  13 CO 2 measured in breath samples. We compared Wagner-Nelson analysis with (i) scintigraphy and (ii) conventional breath test modelling to quantify gastric emptying in type 2 diabetes., Methods: Thirteen patients (age 68.1±1.5 years, body mass index 31.0±0.9 kg/m 2 , HbA1c 6.3±0.2%) consumed a mashed potato meal comprising 65 g powdered potato, 20 g glucose, 250 ml water, an egg yolk labelled with 100 μL 13 C-octanoic acid and 20MBq 99m Tc-calcium phytate. Scintigraphic data were acquired and breath samples collected for 4 hours after the meal. Gastric emptying curves were derived based on each technique; the 50% emptying time and intragastric retention at 60 min were also calculated., Results: With Wagner-Nelson analysis, a K el =0.60 (the elimination constant) best approximated the scintigraphic gastric emptying curve. There was a relationship between the T50 calculated with scintigraphy and by both Wagner-Nelson K el =0.60 (r 2 =0.45, P<0.05) and conventional analysis (r 2 =0.44, P<0.05). There was no significant difference in the 50% gastric emptying time for scintigraphy (68.5±4.8 min) and Wagner-Nelson K el =0.60 (71.3±4.5 min), however, the 50% gastric emptying time calculated by conventional analysis was much greater at 164.7±6.0 min (P<0.001)., Conclusion: In type 2 diabetes, gastric emptying of a mashed potato meal measured using a 13 C-octanoic acid breath test analysed with Wagner-Nelson K el =0.60 closely reflects measurements obtained with scintigraphy, whereas, in absolute terms, the conventional breath test analysis does not., Competing Interests: Michael Nauck has received compensation for lectures or advisory board membership from AstraZeneca, Berlin-Chemie/Menarini, Medscape, Merck Sharp & Dohme, Novo Nordisk, Sanofi-Aventis, Takeda, and Sun Pharma; received grant support from Berlin-Chemie/Menarini, Eli Lilly and Company, Merck Sharp & Dohme, and Novo Nordisk. Tongzhi Wu has received travel support from Novartis and Sanofi and research funding from Novartis and AstraZeneca. Juris Meier has received compensation for lectures or advisory board membership from AstraZeneca, Boehringer-Ingelheim, Berlin-Chemie/Menarini, Eli Lilly, Medscape, Merck Sharp & Dohme, Novo Nordisk, Sanofi; received grant support from Novo Nordisk. Christopher Rayner has received research funding from Sanofi, Novartis, Eli Lilly, Merck Sharp & Dohme, and AstraZeneca. Michael Horowitz has participated in the advisory boards and/or symposia for Novo Nordisk, Sanofi, Novartis, Eli Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, and AstraZeneca and has received honoraria for this activity. Karen Jones has received research funding from Sanofi and AstraZeneca and drug supplies from Merck Sharp & Dohme. Laurence Trahair, Julie Stevens, Madeline Buttfield, Seva Hatzinikolas and Hung Pham have no conflicts of interest to declare., (Thieme. All rights reserved.)

Aims: To evaluate the efficacy and safety of oral semaglutide versus comparators by patient characteristic subgroups in patients with type 2 diabetes., Materials and Methods: Change from baseline in glycated haemoglobin (HbA1c) and body weight, and achievement of HbA1c <7.0% with oral semaglutide 7 mg, oral semaglutide 14 mg, flexibly dosed oral semaglutide (flex) and comparators were assessed across baseline subgroups (age, race, ethnicity, diabetes duration, body mass index and HbA1c) from the PIONEER programme. Treatment differences were analysed using a mixed model for repeated measurements for continuous variables and a logistic regression model for the binary endpoint. Pooled safety data were analysed descriptively., Results: Changes from baseline in HbA1c and body weight, and the odds of achieving HbA1c <7.0%, were greater with oral semaglutide 14 mg/flex (n = 1934) and higher or similar with oral semaglutide 7 mg (n = 823) versus comparators (n = 2077) across most subgroups. Changes in HbA1c with oral semaglutide 14 mg/flex were greater for patients with higher baseline HbA1c (HbA1c >9.0%: -1.7% to -2.6%; HbA1c <8.0%: -0.7% to -1.2%). In some trials, Asian patients experienced greater HbA1c reductions with oral semaglutide 14 mg/flex (-1.5% to -1.8%) than other racial groups (-0.6% to -1.6%). The overall incidence of adverse events (AEs) with oral semaglutide was similar to that with comparators and was consistent across subgroups. More gastrointestinal AEs were observed with oral semaglutide, versus comparators, across subgroups., Conclusions: Oral semaglutide demonstrated consistently greater HbA1c and body weight reductions across a range of patient characteristics, with greater HbA1c reductions seen at higher baseline HbA1c levels., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Individuals with type 1 diabetes and those with depression show differences in the composition of the gut microbiome from that of healthy people. However, these differences have not yet been studied in patients with both diseases. Therefore, we compared the gut microbiome of people with type 1 diabetes with or without depression with matched healthy controls., Methods: A case-control study was conducted in 20 adults with type 1 diabetes (group A), 20 adults with type 1 diabetes and depression (group B), and 20 healthy adults (group C). Gut microbiota composition was determined by sequencing of the V3-V4 region of the bacterial 16S rDNA and alpha and beta diversity was compared between the groups., Results: Groups A and B both showed higher alpha diversity than the healthy control group (P < 0.001) but alpha diversity did not differ significantly between groups A and B. Participants having type 1 diabetes with (P < 0.05) or without comorbid depression (P < 0.001) differed regarding beta diversity from healthy controls but not between each other. Group B (diabetes with depression) had significantly higher abundance of Megaspaera than groups A and C. Both diabetes groups had a higher abundance of Christensenellaceae, Succinivibrionaceae, and Rhodospirillaceae than the healthy group but similar between-group abundances., Conclusions: While differences in alpha and beta diversity and in some bacterial taxa occurred only between participants with diabetes and healthy controls, specific characteristics regarding the abundance of Megasphaera were observed in people with diabetes and comorbid depression. In summary, the study findings indicate a possible involvement of bacterial groups in depression in people with diabetes. The results suggest replication studies in larger samples to verify these findings., (© 2022. The Author(s).)

This paper describes the Digital Responsibility Goals, their purpose, and the associated guiding criteria and their relevance particularly for health. In addition, the document makes a first proposal for measuring digital responsibility.

Aims: To investigate the effect of renal impairment on incretin metabolism in patients with type 2 diabetes mellitus (T2DM) before and after treatment with the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin., Materials and Methods: Long-standing T2DM patients with normal (estimated glomerular filtration rate [eGFR] >90 mL/min/1.73m 2 ) and impaired (eGFR <60 mL/min/1.73m 2 ) renal function on stable treatment with insulin were included. Before and after 8 days of treatment with 5 mg linagliptin once daily, patients underwent a 75-g oral glucose tolerance test (OGTT) and total and intact glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), glucose, insulin, C-peptide and glucagon concentrations were measured. The primary outcome was the difference between the study groups in change of intact GLP-1 concentrations., Results: Of 115 patients screened, 29 were analysed (15 [51.7%] with and 14 [48.3%] without renal impairment). Renal function differed significantly between the groups (101 ± 11 vs. 47 ± 13 mL/min/1.73m 2 ; P < 0.0001), while glycaemic control was similar (glycated haemoglobin 68 ±  5 vs. 66 ± 5 mmol/mol; P = 0.45). Baseline GLP-1 and GIP levels were comparable. Glucose concentrations during the OGTT were significantly lowered by linagliptin treatment in patients with renal impairment (P = 0.017), but not in those with normal renal function (P = 0.17). Treatment with linagliptin resulted in a significant increase in intact GLP-1 and GIP levels in patients with normal (P = 0.048 and P = 0.0001, respectively) and impaired (P = 0.040 and P = 0.0011, respectively) renal function during the OGTT. However, the primary outcome (difference between the groups in change of intact GLP-1 concentrations) was not significant (P = 0.22). Overall, linagliptin was well tolerated., Conclusions: Treatment with linagliptin increases intact incretin levels in patients with T2DM. Impaired renal function does not compromise the effects of linagliptin on active or total incretin levels as well as on glucagon secretion. Thus, treatment with linagliptin is suitable for patients with T2DM, independently of renal function., (© 2022 John Wiley & Sons Ltd.)

Aim: To investigate whether upper gastrointestinal (GI) disease has any effect on the exposure of oral semaglutide, an important consideration given that its absorption occurs primarily in the stomach., Materials and Methods: In an open-label, parallel-group trial (NCT02877355), subjects aged 18-80 years with type 2 diabetes with mild-to-moderate upper GI disease (N = 36; chronic gastritis [n = 5], gastroesophageal reflux disease [n = 8], and both [n = 23]) or without upper GI disease (N = 19) received oral semaglutide 3 mg once daily for 5 days, followed by 7 mg for 5 days. The primary and key supportive endpoints were the area under the semaglutide plasma concentration-time curve (AUC) from 0 to 24 hours after last trial product administration on day 10 (AUC 0-24h,day10 ) and the maximum semaglutide plasma concentration (C max,day10 ), respectively., Results: Semaglutide exposure was not statistically significantly different between subjects with and without upper GI disease. Estimated group ratios (subjects with/without upper GI disease) were 1.18 (95% confidence interval [CI], 0.80, 1.75) for AUC 0-24h,day10 and 1.16 (95% CI, 0.77, 1.76) for C max . Time to C max and semaglutide half-life were similar in subjects with and without upper GI disease. Oral semaglutide was well tolerated; all adverse events were mild-to-moderate, with no withdrawals because of adverse events., Conclusions: There was no significant difference in exposure to oral semaglutide in subjects with or without upper GI disease, hence no dose adjustment is required., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Obesity is a chronic, multifactorial, relapsing disease. Despite multicomponent lifestyle interventions, including pharmacotherapy, maintaining bodyweight loss is challenging for many people. The pathophysiology of obesity is complex, and currently approved pharmacotherapies only target a few of the many pathways involved; thus, single-targeting agents have limited efficacy. Proglucagon-derived peptides, glucagon, and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), represent attractive targets for managing obesity and metabolic disorders because they may have direct roles in multiple mechanisms including satiety, energy homeostasis, and lipolytic activity. Unimolecular dual and triple agonists targeting glucagon and incretin hormone receptors have been shown to promote bodyweight loss, lower glucose levels, and reduce food intake in animal models of obesity. Multiple dual receptor agonists are in clinical development for the treatment of obesity, including GLP-1/GIP and GLP-1/glucagon receptor agonists. The extent to which glucagon contributes to treatment effects remains to be understood, but it may promote bodyweight loss by reducing food intake, while concomitant GLP-1 receptor agonism ensures normal glucose control. Further research is required to fully understand the molecular mechanisms of action and metabolic effects of both dual and triple receptor agonists., (© 2021 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Introduction: iGlarLixi, the once-daily fixed-ratio combination of insulin glargine 100 U/ml and lixisenatide, robustly improves glycaemic control in adults with type 2 diabetes irrespective of previous treatment [oral antihyperglycaemic drugs (OADs), basal insulin or glucagon-like peptide-1 receptor agonists (GLP-1 RAs)]. Sodium-glucose co-transporter-2 inhibitors (SGLT2is) are a recommended treatment option for people with type 2 diabetes with cardiovascular disease, kidney disease and/or heart failure because of their cardio- and renoprotective benefits. Herein, we assessed the effects of concomitant iGlarLixi and SGLT2i therapy., Methods: We conducted subgroup analyses according to SGLT2i use in: (1) adults with suboptimally controlled type 2 diabetes on GLP-1 RAs and OADs switching to iGlarLixi in the 26-week LixiLan-G randomised controlled trial (RCT; NCT02787551) and (2) adults switching to or adding iGlarLixi in a 6-month, retrospective real-world evidence (RWE) observational study using data from the US Optum-Humedica electronic medical records database. Changes in HbA 1c and hypoglycaemia prevalence and event rates were assessed., Results: There were no major differences in baseline characteristics for those who initiated iGlarLixi while already using SGLT2i (n = 346) and those initiating iGlarLixi without concomitant SGLT2i therapy (n = 1285). HbA 1c reductions from baseline to time of assessment and hypoglycaemia prevalence and event rates were similar for iGlarLixi users regardless of SGLT2i therapy., Conclusion: Evidence from an RCT and an RWE analysis supports the efficacy/effectiveness and safety of iGlarLixi when used concomitantly with SGLT2i., Trial Registration: NCT02787551., (© 2021. The Author(s).)

Background: Basal rate profiles in patients with type 1 diabetes on insulin pump therapy are subject to enormous inter-individual heterogeneity. Tools to predict basal rates based on clinical characteristics may facilitate insulin pump therapy., Methods: Data from 339 consecutive in-patients with adult type 1 diabetes on insulin pump therapy were collected. Basal rate tests were performed over 24 hours. A mathematical algorithm to predict individual basal rate profiles was generated by relating the individual insulin demand to selected clinical characteristics in an exploratory cohort of 170 patients. The predicted insulin pump profiles were validated in a confirmatory cohort of 169 patients., Findings: Basal rates (0.27 ± 0.01 IU.d -1. kg -1 ) showed circadian variations with peaks corresponding to the "dawn" and "dusk" phenomena. Age, gender, duration of pump treatment, body-mass-index, HbA 1c , and triacylglycerol concentrations largely predicted the individual basal insulin demand per day (IU/d; exploratory vs prospective cohorts: r 2  = 0.518, P  < .0001). Model-predicted and actual basal insulin rates were not different (exploratory cohort: Δ 0.1 (95% CI -0.9; 1.0 U/d; P  = .95; prospective cohort: Δ -0.5 (95% CI -1.5; 0.6 IU/d; P  = .46). Similarly, precise predictions were possible for each hour of the day. Actual and predicted "dawn" index correlated significantly in the exploratory but not in the confirmatory cohort., Interpretation: Clinical characteristics predict 52% of the variation in individual basal rate profiles, including their diurnal fluctuations. The multivariate regression model can be used to initiate or optimize insulin pump treatment in patients with type 1 diabetes.

Background: Pump-treated patients with type 1 diabetes have widely differing basal insulin infusion profiles. We analyzed consequences of such heterogeneity for glycemic control under fasting conditions., Methods: Data from 339 adult patients with type 1 diabetes on insulin pump therapy undergoing a 24-hour fast (basal rate test) were retrospectively analyzed. Hourly programmed basal insulin infusion rates and plasma glucose concentrations as well as their proportions within, below, or above arbitrarily defined target ranges were assessed for specific periods of the day (eg, 1-7 hours, "dawn" period, 16-19 hours, "dusk" period, reference period 20-1 hours/10-14 hours), by tertiles of a predefined "dawn" index (mean basal insulin infusion rate during the "dawn" divided by the reference periods)., Results: The "dawn" index varied interindividually from 0.7 to 4.4. Basal insulin infusion profiles exhibited substantial differences ( P = .011), especially overnight. Despite higher insulin infusion rates at 4 and 6.45 hours, patients with the most pronounced "dawn" phenomenon exhibited higher plasma glucose concentrations at those time points ( P < .012). Patients with a marked "dawn" phenomenon exhibited a lower probability for low (<4.4 mmol/L) and a higher probability of high values (>7.2 mmol/L) during the dawn period (all P values <.01)., Conclusions: We observe substantial interindividual heterogeneity in the "dawn" phenomenon. However, widely different empirically derived basal insulin infusion profiles appear appropriate for individual patients, as indicated by similar plasma glucose concentrations, mainly in the target range, during a 24-hour fasting period.

Aim: To clarify the distinct effects of a long-acting (liraglutide) and a short-acting (lixisenatide) glucagon-like peptide-1 receptor agonist (GLP-1 RA) on macronutrient intake, gastrointestinal side effects and pancreas function., Materials and Methods: Fifty participants were randomized to either lixisenatide or liraglutide for a treatment period of 10 weeks. Appetite, satiety, macronutrient intake, gastrointestinal symptoms and variables related to pancreatic function and gastric emptying were assessed at baseline and after treatment., Results: Both GLP-1 RAs reduced macronutrient intake similarly. Weight loss and appetite reduction were not related to the delay in gastric emptying or gastrointestinal side effects (P > .05). Lipase increased significantly with liraglutide treatment (by 18.3 ± 4.1 U/L; P = .0001), but not with lixisenatide (-1.8 ± 2.4 U/L; P = .46). Faecal elastase and serum ß-carotin levels (indicators for exocrine pancreas function) improved in both groups (P < .05). Changes in lipase activities did not correlate with gastrointestinal symptoms (P > .05 for each variable)., Conclusions: Both GLP-1 RAs comparably affected body weight, energy and macronutrient intake. Both treatments were associated with indicators of improved exocrine pancreas function. Reductions in appetite and body weight as a result of treatment with short- or long-acting GLP-1 RAs are not driven by changes in gastric emptying or gastrointestinal side effects., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Competing Interests: JM has received lecture honoraria and consulting fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi; has received reimbursement of congress participation fees and travel expenses from Merck Sharp & Dohme, Novo Nordisk, and Sanofi; and has initiated projects supported by Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, and Sanofi. FG has received research support from Eli Lilly, Lifescan, and Takeda; and has provided advisory services to AstraZeneca, Boehringer Ingelheim, Eli Lilly, Lifescan, Merck Sharp & Dohme, Novo Nordisk, Roche Diabetes Care, and Sanofi. BG has received lecture honoraria and provided advisory services to AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, and Novo Nordisk; and has received lecture honoraria from Bristol Myers Squibb. The author declares that this article received funding from Novo Nordisk. The funder had the following involvement in the article: medical writing support.

Despite the successful development of new therapies for the treatment of type 2 diabetes, such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 inhibitors, the search for novel treatment options that can provide better glycaemic control and at reduce complications is a continuous effort. The present Review aims to present an overview of novel targets and mechanisms and focuses on glucose-lowering effects guiding this search and developments. We discuss not only novel developments of insulin therapy (eg, so-called smart insulin preparation with a glucose-dependent mode of action), but also a group of drug classes for which extensive research efforts have not been rewarded with obvious clinical impact. We discuss the potential clinical use of the salutary adipokine adiponectin and the hepatokine fibroblast growth factor (FGF) 21, among others. A GLP-1 peptide receptor agonist (semaglutide) is now available for oral absorption, and small molecules activating GLP-1 receptors appear on the horizon. Bariatric surgery and its accompanying changes in the gut hormonal milieu offer a background for unimolecular peptides interacting with two or more receptors (for GLP-1, glucose-dependent insulinotropic polypeptide, glucagon, and peptide YY) and provide more substantial glycaemic control and bodyweight reduction compared with selective GLP-1 receptor agonists. These and additional approaches will help expand the toolbox of effective medications needed for optimising the treatment of well delineated subgroups of type 2 diabetes or help develop personalised approaches for glucose-lowering drugs based on individual characteristics of our patients., Competing Interests: Declaration of interests MAN has been a member on advisory boards or has consulted with AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Menarini/Berlin Chemie, Merck, Sharp & Dohme, and NovoNordisk. He has received grant support from AstraZeneca, Eli Lilly, Menarini/Berlin-Chemie, Merck, Sharp & Dohme, and NovoNordisk. He has also served on the speakers' bureau of AstraZeneca, Boehringer Ingelheim, Eli Lilly, Menarini/Berlin Chemie, Merck, Sharp & Dohme, and NovoNordisk. JJM has received consulting and speaker honoraria from AstraZeneca, Eli Lilly, Merck, Sharp & Dohme, Novo Nordisk, Sanofi, and Servier. He has received research support from Boehringer Ingelheim, Eli Lilly, Merck, Sharp & Dohme, Novo Nordisk, and Sanofi. JW has declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Despite the benefits of early and effective glycemic control in the management of type 2 diabetes (T2D), achieving glycated hemoglobin (HbA 1c ) targets is challenging in some patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) provide effective reductions in HbA 1c and body weight. Semaglutide is the only GLP-1RA that is available in both an injectable and oral formulation. The efficacy of once-weekly subcutaneous semaglutide and once-daily oral semaglutide has been investigated in the global SUSTAIN and PIONEER phase III clinical trial programs in a range of clinical settings, including early T2D managed with diet and exercise only, more established T2D uncontrolled on one to three oral antidiabetic drugs, and advanced disease treated with insulin. Across the SUSTAIN program, once-weekly subcutaneous semaglutide 1.0 mg reduced HbA 1c by 1.5-1.8% after 30-56 weeks, which was significantly more than sitagliptin, liraglutide, exenatide extended release, dulaglutide, canagliflozin, or insulin glargine. Across the PIONEER program, once-daily oral semaglutide 14 mg reduced HbA 1c by 1.0-1.4%, significantly more than sitagliptin or empagliflozin, and to a similar extent as liraglutide after 26 weeks. In addition, subcutaneous semaglutide reduced body weight significantly more than all active comparators tested, while oral semaglutide reduced body weight more than sitagliptin and liraglutide, and to a similar extent as empagliflozin. Neither formulation of semaglutide has been associated with an increased risk of hypoglycemia and both improve various measures of health-related quality of life. Semaglutide offers the benefits of a highly effective GLP-1RA in both injectable and oral formulations. Selection of the most appropriate formulation can be made on an individual basis to best suit the patient's preferences and needs., Competing Interests: JJM has received lecture honoraria and consulting fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, and Sanofi; has received reimbursement of congress participation fees and travel expenses from MSD, Novo Nordisk, and Sanofi; and has initiated projects supported by Boehringer Ingelheim, MSD, Novo Nordisk, and Sanofi. The author declares that this article received funding from Novo Nordisk. The funder had the following involvement in the article: medical writing support., (Copyright © 2021 Meier.)

Background: GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.)., Scope of Review: To summarize current knowledge about GLP-1 receptor agonist., Major Conclusions: At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA 1c , both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA 1c  reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Acute bacterial skin and skin structures infections (ABSSSIs) are associated with high morbidity, costs and mortality in patients with diabetes mellitus. Their appropriate management should include several figures and a well-organized approach. This review aims to highlight the interplay between diabetes and ABSSSIs and bring out the unmet clinical needs in this area. Pathogenetic mechanisms underlying the increased risk of ABSSSIs in diabetes mellitus are multifactorial: high glucose levels play a crucial pathogenetic role in the tissue damage and delayed clinical cure. Moreover, the presence of diabetes complications (neuropathy, vasculopathy) further complicates the management of ABSSSIs in patients with diabetes. Multidrug resistance organisms should be considered in this population based on patient risk factors and local epidemiology and etiological diagnosis should be obtained whenever possible. Moreover, drug-drug interactions and drug-related adverse events (such as nephrotoxicity) should be considered in the choice of antibiotic therapy. Reducing unnecessary hospitalizations and prolonged length of hospital stay is of primary importance now, more than ever. To achieve these objectives, a better knowledge of the interplay between acute and chronic hyperglycemia, multidrug resistant etiology, and short and long-term outcome is needed. Of importance, a multidisciplinary approach is crucial to achieve full recovery of these patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘MF received speaker honoraria for Angelini, MSD, Pfizer, and Nordic Pharma. JJM received personal fees from Astra Zeneca, Boehringer-Ingelheim, Eli Lilly, MSD, Novo Nordisk, Sanofi, Servier. JMA has received honoraria for speaking at symposia organized on behalf of Pfizer, Astellas, Merck Sharp & Dohme (MSD), Angelini, and Gilead Science and has sat on advisory boards on behalf of Pfizer, Astellas, MSD, Angelini, and Gilead Science. SDP reports grants and/or personal fees from Boehringer Ingelheim, Astra Zeneca, Novo Nordisk, Eli Lilly, GlaxoSmitheKline, MSD, Novartis Pharmaceuticals, Sanofi, Takeda. FM has participated in advisory boards and/or received speaker honoraria from Angelini, Correvio, MSD, Pfizer, Astellas, Gilead, BMS, Jansenn, ViiV, BioMerieux, Biotest, Becton-Dickinson, Nordic Pharma, Pfizer, Shionogi. All COI are outside the submitted study. All authors disclose personal fees from Ethos, during the conduct of the study.’, (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Twenty-four hour fasting periods are being used to scrutinize basal insulin infusion rates for pump-treated patients with type 1 diabetes., Methods: Data from 339 consecutive in-patients with adult type 1 diabetes on insulin pump therapy undergoing a 24-hour fast as a basal rate test were retrospectively analyzed. Hourly programmed basal insulin infusion rates and plasma glucose concentrations within, below, or above arbitrarily defined target ranges were assessed for periods of the day of special interest (eg, 01:00-07:00 am, "dawn" period, 04:00-07:00 pm, and "dusk" period). Statistics: χ 2 -tests, paired t-tests were used., Results: Basal rates (mean: 0.90 ± 0.02 IU/h) showed circadian variations with peaks corresponding to "dawn" (1.07 ± 0.02 IU/h from 01:00 to 07:00 am) and, less prominently, "dusk" (0.95 ± 0.02 IU/h from 03:00 to 07:00 pm). Individual mean plasma glucose concentrations averaged 6.6 ± 0.1 mmol/L, with 53.1% in the predefined "strict" (4.4-7.2 mmol/L) target range. Interestingly, during the "dawn" period, plasma glucose was significantly higher (by 0.5 ± 0.1 mmol/L [95% confidence interval: 0.3-0.8 mmol/L; P < .0001]) and the odds ratio for hypoglycemia was significantly lower compared to the reference period., Interpretation: Twenty-four hour fasting periods as basal rate tests frequently unravel periods with inappropriate basal insulin infusion rates potentially responsible for fasting hyper- or hypoglycemia. Notably, the higher basal insulin infusion rate found during the "dawn" period seems to be justified and may need to be accentuated.

Objective: Acute experimental variations in glycemia decelerate (hyperglycemia) or accelerate (hypoglycemia) gastric emptying. Whether spontaneous variations in fasting plasma glucose (FPG) have a similar influence on gastric emptying is yet unclear., Research Design and Methods: Gastric emptying of a mixed meal was prospectively studied three times in 20 patients with type 1 diabetes and 10 healthy subjects with normal glucose tolerance using a 13 C-CO 2 octanoate breath test with Wagner-Nelson analysis. The velocity of gastric emptying was related to FPG measured before the test (grouped as low, intermediate, or high). In addition, gastric emptying data from 255 patients with type 1 diabetes studied for clinical indications were compared by tertiles of baseline FPG., Results: Despite marked variations in FPG (by 4.8 [95% CI 3.4; 6.2] mmol/L), gastric emptying did not differ among the three prospective examinations in patients with type 1 diabetes (Δ T 1/2 between highest and lowest FPG: 1 [95% CI -35; 37] min; P = 0.90). The coefficient of variation for T 1/2 determined three times was 21.0%. Similar results at much lower variations in FPG were found in healthy subjects. In the cross-sectional analysis, gastric emptying did not differ between the tertiles of FPG (Δ T 1/2 between highest and lowest FPG: 7 [95% CI -10; 23] min; P = 0.66), when FPG varied by 7.2 (6.7; 7.8) mmol/L. However, higher HbA 1c was significantly related to slower gastric emptying., Conclusions: Day-to-day variations in FPG not induced by therapeutic measures do not influence gastric emptying significantly. These findings are in contrast with those obtained after rapidly clamping plasma glucose in the hyper- or hypoglycemic concentrations range and challenge the clinical importance of short-term glucose fluctuations for gastric emptying in patients with type 1 diabetes. Rather, chronic hyperglycemia is associated with slowed gastric emptying., (© 2020 by the American Diabetes Association.)

Objective: Short-acting glucagon-like peptide 1 receptor agonists (GLP-1 RAs) decelerate gastric emptying more than long-acting GLP-1 RAs. Delayed gastric emptying is a risk factor for gastroesophageal reflux disease. We aimed to measure esophageal reflux and function as well as gastric emptying and acid secretion during treatment with short-acting (lixisenatide) and long-acting (liraglutide) GLP-1 RAs., Research Design and Methods: A total of 57 subjects with type 2 diabetes were randomized to a 10-week treatment with lixisenatide or liraglutide. Changes from baseline in the number of reflux episodes during 24-h pH registration in the lower esophagus, lower esophagus sphincter pressure, gastric emptying ( 13 C-sodium octanoate acid breath test), and gastric acid secretion ( 13 C-calcium carbonate breath test) were analyzed., Results: Gastric emptying half-time was delayed by 52 min (Δ 95% CI 16, 88) with lixisenatide ( P = 0.0065) and by 25 min (3, 46) with liraglutide ( P = 0.025). There was no difference in the number of reflux episodes (mean ± SEM 33.7 ± 4.1 vs. 40.1 ± 5.3 for lixisenatide and liraglutide, respectively, P = 0.17) or the extent of gastroesophageal reflux (DeMeester score) (35.1 ± 6.7 vs. 39.7 ± 7.5, P = 0.61), with similar results for the individual GLP-1 RAs. No significant changes from baseline in other parameters of esophageal motility and lower esophageal sphincter function were observed. Gastric acidity decreased significantly by -20.7% (-40.6, -0.8) ( P = 0.042) with the GLP-1 RAs., Conclusions: Lixisenatide exerted a more pronounced influence on gastric emptying after breakfast than liraglutide. Neither lixisenatide nor liraglutide had significant effects on esophageal reflux or motility. Gastric acid secretion appears to be slightly reduced by GLP-1 RAs., (© 2020 by the American Diabetes Association.)

Purpose: To compare the efficacy and safety of short- and long-acting glucagon-like peptide 1 receptor agonists (GLP-1 RAs), both used in combination with basal insulin, in patients with type 2 diabetes., Data Sources and Study Selection: Randomized controlled trials comparing the coadministration of short- or long-acting GLP-1 RAs and basal insulin with basal insulin ± placebo were identified (PubMed search). Of 974 identified publications, 14 clinical trials were included. Eight trials examined short-acting and six long-acting GLP-1 RAs., Data Extraction and Data Synthesis: Differences in HbA 1c , fasting plasma glucose, body weight, and adverse events were compared between studies using short- or long-acting GLP-1 RAs by random-effects meta-analysis., Limitations: There were relatively small numbers of available publications, some heterogeneity regarding protocols, and differences in the GLP-1 RA compound used., Conclusions: Long-acting GLP-1 RAs more effectively reduced HbA 1c (∆ -6 mmol/mol [95% CI -10; -2], P = 0.007), fasting plasma glucose (∆ -0.7 mmol/L [-1.2; -0.3], P = 0.007), and body weight (∆ -1.4 kg [-2.2; -0.6], P = 0.002) and raised the proportion of patients achieving an HbA 1c target <7.0% (<53 mmol/mol) ( P = 0.03) more than the short-acting ones. Patients reporting symptomatic ( P = 0.048) but not severe ( P = 0.96) hypoglycemia were fewer with long- versus short-acting GLP-1 RAs added to insulin. A lower proportion of patients reported nausea (-52%, P < 0.0001) or vomiting (-36%, P = 0.0002) with long-acting GLP-1 RAs. Overall, GLP-1 RAs improved HbA 1c , fasting plasma glucose, and body weight when added to basal insulin. However, long-acting GLP-1 RAs were significantly more effective for glycemic and body weight control and displayed better gastrointestinal tolerability., (© 2020 by the American Diabetes Association.)

Aims: We aimed to quantify the exposure to physical exercise associated with professional, recreational, or traffic-related activities in patients with type 2 diabetes, which may provoke or aggravate hypoglycaemic episodes, and to assess whether such risks determine the choice of medications minimizing the risk of hypoglycaemia., Methods: In total, 203 patients with type 2 diabetes (98 women, 105 men, age 65 [56;72; median, inter-quartile range] years, diabetes duration 10 [5;15] years) were recruited from a German diabetes practice. A questionnaire assessed their engagement in professional, recreational, or traffic-related activities. The prescription insulin or sulphonylureas was quantified in relation to the number of such activities., Results: 63.5% of the patients were treated with insulin, 7.4% with sulphonylureas, and 70.9% with either. Sixty-six patients (22.7%) were professionally active: 36 (54.4%) of those were professionally exposed to risky behaviour (14 [31.8%] patients with exposure to multiple risks and 20 (30.3%) who experienced hypoglycaemic episodes in the past year). In total, 194 (95.6%) patients were exposed to risky behaviour during recreational activities, 129 (63.6%) to multiple ones. All patients were exposed to traffic-related activities, 144 (70.9%) were exposed to more than being pedestrian, and 24 (11.8%) experienced hypoglycaemic episodes while in traffic., Conclusions: Patients with type 2 diabetes are exposed to risks associated with professional, recreational, and traffic-related activities. We recommend a careful assessment of such risks before glucose-lowering medications with a potential for provoking hypoglycaemic episodes are prescribed.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended for glycaemic management in patients with type 2 diabetes (T2D). Oral semaglutide, the first oral GLP-1RA, has recently been approved for clinical use, based on the results of the randomized, Phase 3a Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) clinical trials. The PIONEER programme tested oral semaglutide in patients with T2D of duration ranging from 3.5 to 15 years, from monotherapy through to insulin add-on, in global populations and two trials dedicated to Japanese patients. Outcomes (glycated haemoglobin [HbA1c] and body weight reduction, plus other relevant efficacy and safety endpoints) were tested against both placebo and active standard-of-care medications. A separate trial evaluated the cardiovascular safety of oral semaglutide in patients with T2D at high cardiovascular risk. Over periods of treatment up to 78 weeks, oral semaglutide 7 and 14 mg once daily reduced HbA1c and body weight across the spectrum of T2D, and improved other diabetes-related endpoints, such as fasting plasma glucose. Oral semaglutide provided significantly better efficacy than placebo and commonly used glucose-lowering medications from the dipeptidyl peptidase-4 inhibitor (sitagliptin) and sodium-glucose co-transporter-2 inhibitor (empagliflozin) classes, as well as the subcutaneous GLP-1RAs liraglutide and dulaglutide. Oral semaglutide was well tolerated in line with the known safety profile of GLP-1RAs, with transient gastrointestinal events being the most common side effects reported. Cardiovascular safety was demonstrated for oral semaglutide in patients with cardiovascular disease or high cardiovascular risk. The results of the PIONEER programme suggest that oral semaglutide is efficacious and well tolerated for glycaemic control of T2D. The availability of oral semaglutide may help to broaden treatment choice and facilitate adoption of earlier GLP-1RA treatment in the paradigm of T2D management., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Amyloid deposits are a typical finding in pancreatic islets from patients with type 2 diabetes. Whether this is linked to the pathogenesis of type 2 diabetes is currently unknown. Therefore, we compared the occurrence of islet amyloid in patients with type 2 diabetes, diabetes secondary to pancreatic disorders, and nondiabetic individuals., Patients and Methods: Pancreatic tissue from 15 nondiabetic patients, 22 patients with type 2 diabetes, and 11 patients with diabetes due to exocrine pancreatic disorders (chronic pancreatitis, pancreatic carcinoma) were stained for insulin, amyloid, and apoptosis. β-cell area, amyloid deposits, and β-cell apoptosis were quantified by morphometric analysis., Results: The proportion of islets containing amyloid deposits was significantly higher in both type 2 diabetes and diabetes due to exocrine pancreatic disorders than in healthy subjects. Islets with both amyloid and apoptosis were observed more frequently in type 2 diabetes and significantly more so in diabetes due to exocrine pancreatic disorders. In both diabetic groups, apoptotic ß-cells were found significantly more frequently in islets with more prominent amyloid deposits., Conclusions: The occurrence of amyloid deposits in both type 2 diabetes and diabetes secondary to exocrine pancreatic disorders suggests that islet amyloid formation is a common feature of diabetes mellitus of different etiologies and may be associated with a loss of pancreatic ß-cells., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Some epidemiological data have suggested an elevated risk of acute pancreatitis and pancreatic cancer after exposure to glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors. Recently, such outcomes have been assessed and adjudicated as adverse events of special interest in cardiovascular outcomes studies. We performed a meta-analysis of cases of acute pancreatitis and pancreatic cancer as well as any malignant neoplasm reported in cardiovascular outcomes trials (CVOTs) with GLP-1 receptor agonists and DPP-4 inhibitors. The numbers of cases observed with active drug or placebo (both on a background of standard care) were related to patient-years of observation. Rate ratios and their confidence intervals were calculated for the individual agents as well as for the classes of GLP-1 receptor agonists and DPP-4 inhibitors. Neither data on individual CVOTs of GLP-1 receptor agonists nor their meta-analysis [rate ratio: 1.05 (0.78-1.41)] indicated a significantly elevated risk of acute pancreatitis. All individual DPP-4 inhibitors displayed a non-significant trend towards an increased risk of acute pancreatitis, which was significant in the meta-analysis [1.75 (1.14-2.70); P = 0.01]. Neither GLP-1 receptor agonists nor DPP-4 inhibitors were associated with a significantly elevated or reduced risk of pancreatic cancer or for the totality of all malignant neoplasms. Based on a large database of randomized, placebo-controlled, prospective cardiovascular outcomes studies with GLP-1 receptor agonists and DPP-4 inhibitors, no signal for pancreatic cancer or any malignant neoplasms were detected. However, a 75% risk increase for the development of an acute pancreatitis was seen in the meta-analysis of DPP-4 inhibitor CVOTs., (© 2019 John Wiley & Sons Ltd.)

Aim: To examine the glucose-lowering mechanisms of the glucagon-like peptide-1 receptor agonist lixisenatide after two subsequent meals and in combination with basal insulin., Materials and Methods: Twenty-eight metformin-treated patients with type 2 diabetes were randomly assigned to treatment sequences with either lixisenatide or insulin glargine alone for 4 weeks, and a combination of both treatments for 4 weeks. Metabolic examinations were performed before and after each treatment period following breakfast and a late lunch 8 hours later., Results: Lixisenatide mainly reduced postprandial glycaemia, while insulin glargine mainly reduced fasting glucose after breakfast (P < 0.05). This was partially preserved after a late lunch (P < 0.05). After breakfast, lixisenatide reduced insulin secretion and glucagon levels significantly. These effects were lost after a late lunch. Insulin glargine did not significantly reduce glucagon or insulin secretion. Gastric emptying was slowed by lixisenatide, but not by insulin glargine after breakfast. After the late lunch, lixisenatide slightly accelerated gastric emptying., Conclusions: Lixisenatide decelerates gastric emptying after breakfast, thereby reducing glycaemic excursions, insulin secretion and glucagon levels. The glycaemic reduction persists until after a late lunch, despite accelerated gastric emptying. The combination with insulin glargine enhances the glucose-lowering effect because of complementary modes of action., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)