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Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) were first introduced for the treatment of type 2 diabetes (T2D) in 2005. Despite the high efficacy and other benefits of GLP-1RAs, their uptake was initially limited by the fact that they could only be administered by injection. Semaglutide is a human GLP-1 analog that has been shown to significantly improve glycemic control and reduce body weight, in addition to improving cardiovascular outcomes, in patients with T2D. First approved as a once-weekly subcutaneous injection, semaglutide was considered an ideal peptide candidate for oral delivery with a permeation enhancer on account of its low molecular weight, long half-life, and high potency. An oral formulation of semaglutide was therefore developed by co-formulating semaglutide with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, a well-characterized transcellular permeation enhancer, to produce the first orally administered GLP-1RA. Pharmacokinetic analysis showed that stable steady-state concentrations could be achieved with once-daily dosing owing to the long half-life of oral semaglutide. Upper gastrointestinal disease and renal and hepatic impairment did not affect the pharmacokinetic profile. In the phase III PIONEER clinical trial program, oral semaglutide was shown to reduce glycated hemoglobin and body weight compared with placebo and active comparators in patients with T2D, with no new safety signals reported. Cardiovascular efficacy and safety are currently being assessed in a dedicated outcomes trial. The development of an oral GLP-1RA represents a significant milestone in the management of T2D, providing an additional efficacious treatment option for patients.

The gut microbiome is emerging as a key modulator of human energy balance. Prior studies in humans lacked the environmental and dietary controls and precision required to quantitatively evaluate the contributions of the gut microbiome. Using a Microbiome Enhancer Diet (MBD) designed to deliver more dietary substrates to the colon and therefore modulate the gut microbiome, we quantified microbial and host contributions to human energy balance in a controlled feeding study with a randomized crossover design in young, healthy, weight stable males and females (NCT02939703). In a metabolic ward where the environment was strictly controlled, we measured energy intake, energy expenditure, and energy output (fecal and urinary). The primary endpoint was the within-participant difference in host metabolizable energy between experimental conditions [Control, Western Diet (WD) vs. MBD]. The secondary endpoints were enteroendocrine hormones, hunger/satiety, and food intake. Here we show that, compared to the WD, the MBD leads to an additional 116 ± 56 kcals (P < 0.0001) lost in feces daily and thus, lower metabolizable energy for the host (89.5 ± 0.73%; range 84.2-96.1% on the MBD vs. 95.4 ± 0.21%; range 94.1-97.0% on the WD; P < 0.0001) without changes in energy expenditure, hunger/satiety or food intake (P > 0.05). Microbial 16S rRNA gene copy number (a surrogate of biomass) increases (P < 0.0001), beta-diversity changes (whole genome shotgun sequencing; P = 0.02), and fermentation products increase (P < 0.01) on an MBD as compared to a WD along with significant changes in the host enteroendocrine system (P < 0.0001). The substantial interindividual variability in metabolizable energy on the MBD is explained in part by fecal SCFAs and biomass. Our results reveal the complex host-diet-microbiome interplay that modulates energy balance. The gut microbiome is causally linked to body weight in preclinical models. Here, in a controlled feeding study, the authors show that greater delivery of gut-microbiome fermentable dietary substrates to the colon leads to a net negative energy balance that is accompanied by robust microbial and host responses.

Aims/hypothesisThe double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality.MethodsIn DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population.ResultsThere was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group.Conclusions/interpretationThe results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect.Trial registrationClinicalTrials.gov NCT01959529

Agonists of the glucagon-like peptide-1 (GLP-1) receptor provide pharmacological levels of GLP-1 activity, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors increase concentrations of endogenous GLP-1 and glucose-dependent insulinotropic polypeptide. We aimed to assess the efficacy and safety of the human GLP-1 analogue liraglutide versus the DPP-4 inhibitor sitagliptin, as adjunct treatments to metformin, in individuals with type 2 diabetes who did not achieve adequate glycaemic control with metformin alone. In this parallel-group, open-label trial, participants (aged 18–80 years) with type 2 diabetes mellitus who had inadequate glycaemic control (glycosylated haemoglobin [HbA 1c] 7·5–10·0%) on metformin (≥1500 mg daily for ≥3 months) were enrolled and treated at office-based sites in Europe, the USA, and Canada. Participants were randomly allocated to receive 26 weeks' treatment with 1·2 mg (n=225) or 1·8 mg (n=221) subcutaneous liraglutide once daily, or 100 mg oral sitagliptin once daily (n=219). The primary endpoint was change in HbA 1c from baseline to week 26. The efficacy of liraglutide versus sitagliptin was assessed hierarchically by a non-inferiority comparison, with a margin of 0·4%, followed by a superiority comparison. Analyses were done on the full analysis set with missing values imputed by last observation carried forward; seven patients assigned to liraglutide did not receive treatment and thus did not meet criteria for inclusion in the full analysis set. This trial is registered with ClinicalTrials.gov, number NCT00700817. Greater lowering of mean HbA 1c (8·5% at baseline) was achieved with 1·8 mg liraglutide (−1·50%, 95% CI −1·63 to −1·37, n=218) and 1·2 mg liraglutide (−1·24%, −1·37 to −1·11, n=221) than with sitagliptin (−0·90%, −1·03 to −0·77, n=219). Estimated mean treatment differences for liraglutide versus sitagliptin were −0·60% (95% CI −0·77 to −0·43, p<0·0001) for 1·8 mg and −0·34% (−0·51 to −0·16, p<0·0001) for 1·2 mg liraglutide. Nausea was more common with liraglutide (59 [27%] patients on 1·8 mg; 46 [21%] on 1·2 mg) than with sitagliptin (10 [5%]). Minor hypoglycaemia was recorded in about 5% of participants in each treatment group. Liraglutide was superior to sitagliptin for reduction of HbA 1c, and was well tolerated with minimum risk of hypoglycaemia. These findings support the use of liraglutide as an effective GLP-1 agent to add to metformin. Novo Nordisk.

Background Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia. Paradoxically, some interventional studies in humans and rodents have shown unfavorable changes in glucose homeostasis in response to NCAS consumption. The causative mechanisms are largely unknown, but adverse changes in gut microbiota have been proposed to mediate these effects. These findings have raised concerns about NCAS safety and called into question their broad use, but further physiological and dietary considerations must be first addressed before these results are generalized. We also reasoned that, since NCAS are bona fide ligands for sweet taste receptors (STRs) expressed in the intestine, some metabolic effects associated with NCAS use could be attributed to a common mechanism involving the host. Results We conducted a double-blind, placebo-controlled, parallel arm study exploring the effects of pure saccharin compound on gut microbiota and glucose tolerance in healthy men and women. Participants were randomized to placebo, saccharin, lactisole (STR inhibitor), or saccharin with lactisole administered in capsules twice daily to achieve the maximum acceptable daily intake for 2 weeks. In parallel, we performed a 10-week study administering pure saccharin at a high dose in the drinking water of chow-fed mice with genetic ablation of STRs (T1R2-KO) and wild-type (WT) littermate controls. In humans and mice, none of the interventions affected glucose or hormonal responses to an oral glucose tolerance test (OGTT) or glucose absorption in mice. Similarly, pure saccharin supplementation did not alter microbial diversity or composition at any taxonomic level in humans and mice alike. No treatment effects were also noted in readouts of microbial activity such as fecal metabolites or short-chain fatty acids (SCFA). However, compared to WT, T1R2-KO mice were protected from age-dependent increases in fecal SCFA and the development of glucose intolerance. Conclusions Short-term saccharin consumption at maximum acceptable levels is not sufficient to alter gut microbiota or induce glucose intolerance in apparently healthy humans and mice. Trial registration Trial registration number NCT03032640 , registered on January 26, 2017. 3ThJTRkvKM2w8o53nrbAga Video abstract

DEVOTE was designed to evaluate the cardiovascular safety of insulin degludec (IDeg) vs insulin glargine U100 (IGlar) in patients with T2D at high risk of cardiovascular events. DEVOTE is a phase 3b, multicenter, international, randomized, double-blind, active comparator-controlled trial, designed as an event-driven trial that would continue until 633 positively adjudicated primary events were accrued. The primary end point was the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Patients with T2D at high risk of cardiovascular complications were randomized 1:1 to receive either IDeg or IGlar, each added to background therapies. This trial was designed to demonstrate statistical noninferiority of IDeg vs IGlar for the primary end point. DEVOTE enrolled 7,637 patients between October 2013 and November 2014 at 436 sites in 20 countries. Of these, 6,506 patients had prior cardiovascular disease or chronic kidney disease, and the remainder had multiple cardiovascular risk factors. DEVOTE was designed to provide conclusive evidence regarding the cardiovascular safety of IDeg relative to IGlar in a high-risk population of patients with T2D.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the SARS-CoV-2 virus, is wreaking havoc around the world. Considering that extracellular vesicles (EVs) released from SARS-CoV-2 infected cells might play a role in a viremic phase contributing to disease progression and that standard methods for EV isolation have been reported to co-isolate viral particles, we would like to recommend the use of heightened laboratory safety measures during the isolation of EVs derived from SARS-CoV-2 infected tissue and blood from COVID-19 patients. Research needs to be conducted to better understand the role of EVs in SARS-CoV-2 infectivity, disease progression, and transmission. EV isolation procedures should include approaches for protection from SARS-CoV-2 contamination. We recommend the EV and virology scientific communities develop collaborative projects where relationships between endogenous EVs and potentially lethal enveloped viruses are addressed to better understand the risks and pathobiology involved.

ABSTRACT Background: Glucagon-like peptide-1 (GLP‑1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones secreted by the enteroendocrine cells of the gut in response to the ingestion of nutrients. These incretin hormones, so called because they increase insulin secretion, are key modulators of pancreatic islet hormone secretion and, thus, glucose homeostasis. The glucoregulatory effects of incretins are the basis for new therapies currently being developed for the treatment of type 2 diabetes mellitus (T2DM). Drugs that inhibit dipeptidyl peptidase-4 (DPP‑4), a ubiquitous enzyme that rapidly inactivates both GLP-1 and GIP, increase active levels of these hormones and, in doing so, improve islet function and glycemic control in T2DM. Scope: In this review, we briefly describe (1) the role of pancreatic islet dysfunction in the onset and progression of T2DM, (2) the rationale for developing drugs that enhance incretin activity, (3) the evidence that inhibition of DPP‑4 is effective in ameliorating islet dysfunction and improving glycemic control in T2DM, (4) the efficacy, safety, and tolerability of DPP‑4 inhibitors as monotherapy and in combination with other antidiabetic agents, and (5) the potential utility of DPP‑4 inhibitors relative to existing oral antidiabetic agents and newer antidiabetic drugs in the pipeline. The review is based upon MEDLINE literature searches (1966–August 2006) and abstracts and presentations from the American Diabetes Association Scientific Sessions (2002–2006) and the European Association for the Study of Diabetes Annual Meetings (1998–2006). Basic science, preclinical, and clinical studies and review articles published in the English language were evaluated and selected based upon consideration of their originality, relevance, and frequency of citation. Findings: DPP‑4 inhibitors are a new class of antidiabetogenic drugs that provide comparable efficacy to current treatments. They are effective as monotherapy in patients inadequately controlled with diet and exercise and as add-on therapy in combination with metformin, thiazolidinediones, and insulin. The DPP‑4 inhibitors are well tolerated, carry a low risk of producing hypoglycemia, and are weight-neutral. The long-term durability of effect on glycemic control and β‑cell morphology and function remain to be established. Conclusions: Islet cell dysfunction is central to the pathogenesis of T2DM. Incretin-based therapies, including GLP-1 analogues and DPP‑4 inhibitors, have been shown to restore glucose homeostasis and improve glycemic control. The DPP‑4 inhibitors, which can be used as monotherapy or in combination with other antidiabetic drugs, are a promising new treatment option, especially for patients with early-stage T2DM and more severe hyperglycemia.

IntroductionHemoglobin glycation index (HGI) is the difference between observed and predicted glycated hemoglobin A1c (HbA1c), derived from mean or fasting plasma glucose (FPG). In this secondary, exploratory analysis of data from DEVOTE, we examined: whether insulin initiation/titration affected the HGI; the relationship between baseline HGI tertile and cardiovascular and hypoglycemia risk; and the relative strengths of HGI and HbA1c in predicting these risks.Research design and methodsIn DEVOTE, a randomized, double-blind, cardiovascular outcomes trial, people with type 2 diabetes received once per day insulin degludec or insulin glargine 100 units/mL. The primary outcome was time to first occurrence of a major adverse cardiovascular event (MACE), comprising cardiovascular death, myocardial infarction or stroke; severe hypoglycemia was a secondary outcome. In these analyses, predicted HbA1c was calculated using a linear regression equation based on DEVOTE data (HbA1c=0.01313 FPG (mg/dL) (single value)+6.17514), and the population data were grouped into HGI tertiles based on the calculated HGI values. The distributions of time to first event were compared using Kaplan–Meier curves; HRs and 95% CIs were determined by Cox regression models comparing risk of MACE and severe hypoglycemia between tertiles.ResultsChanges in HGI were observed at 12 months after insulin initiation and stabilized by 24 months for the whole cohort and insulin-naive patients. There were significant differences in MACE risk between baseline HGI tertiles; participants with high HGI were at highest risk (low vs high, HR: 0.73 (0.61 to 0.87)95% CI; moderate vs high, HR: 0.67 (0.56 to 0.81)95% CI; p<0.0001). No significant differences between HGI tertiles were observed in the risk of severe hypoglycemia (p=0.0911). With HbA1c included within the model, HGI no longer significantly predicted MACE.ConclusionsHigh HGI was associated with a higher risk of MACE; this finding is of uncertain significance given the association of HGI with insulin initiation and HbA1c.Trial registration numberNCT01959529.

IntroductionEven with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper c ortisolism in P at ients with Difficult to Control Type 2 Di a betes Despite Receiving Standard-of-Care Therapies: Preva l ence and Treatment with Korl y m® (Mifepri st one) (CATALYST) trial.Methods and analysisIn part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%–11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym®). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life.Ethics and disseminationThe study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals.Trial registration number NCT05772169.