Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial.

AIMS: To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon-like peptide-1 receptor agonist. MATERIALS AND METHODS: PIONEER 6 is a multinational, randomized, placebo-controlled, double-blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once-daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non-fatal myocardial infarction or non-fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non-inferiority versus placebo for the primary endpoint (non-inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event-driven, with follow-up continuing until accrual of at least 122 primary outcome events. There is no pre-defined minimal duration. RESULTS: Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD. CONCLUSIONS: PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.

Switching to Once-Weekly Insulin Icodec Versus Once-Daily Insulin Glargine U100 in Type 2 Diabetes Inadequately Controlled on Daily Basal Insulin: A Phase 2 Randomized Controlled Trial.

OBJECTIVE: Insulin icodec (icodec) is a novel once-weekly basal insulin analog. This trial investigated two approaches for switching to icodec versus once-daily insulin glargine 100 units/mL (IGlar U100) in people with type 2 diabetes receiving daily basal insulin and one or more oral glucose-lowering medications. RESEARCH DESIGN AND METHODS: This multicenter, open-label, treat-to-target phase 2 trial randomized (1:1:1) eligible basal insulin-treated (total daily dose 10-50 units) people with type 2 diabetes (HbA1c 7.0-10.0% [53.0-85.8 mmol/mol]) to icodec with an initial 100% loading dose (in which only the first dose was doubled [icodec LD]), icodec with no loading dose (icodec NLD), or IGlar U100 for 16 weeks. Primary end point was percent time in range (TIR; 3.9-10.0 mmol/L [70-180 mg/dL]) during weeks 15 and 16, measured using continuous glucose monitoring. Key secondary end points included HbA1c, adverse events (AEs), and hypoglycemia. RESULTS: Estimated mean TIR during weeks 15 and 16 was 72.9% (icodec LD; n = 54), 66.0% (icodec NLD; n = 50), and 65.0% (IGlar U100; n = 50), with a statistically significant difference favoring icodec LD versus IGlar U100 (7.9%-points [95% CI 1.8-13.9]). Mean HbA1c reduced from 7.9% (62.8 mmol/mol) at baseline to 7.1% (54.4 mmol/mol icodec LD) and 7.4% (57.6 mmol/mol icodec NLD and IGlar U100); incidences and rates of AEs and hypoglycemic episodes were comparable. CONCLUSIONS: Switching from daily basal insulin to once-weekly icodec was well tolerated and provided effective glycemic control. Loading dose use when switching to once-weekly icodec significantly increased percent TIR during weeks 15 and 16 versus once-daily IGlar U100, without increasing hypoglycemia risk.

The Endocannabinoid System of Animals.

The endocannabinoid system has been found to be pervasive in mammalian species. It has also been described in invertebrate species as primitive as the Hydra. Insects, apparently, are devoid of this, otherwise, ubiquitous system that provides homeostatic balance to the nervous and immune systems, as well as many other organ systems. The endocannabinoid system (ECS) has been defined to consist of three parts, which include (1) endogenous ligands, (2) G-protein coupled receptors (GPCRs), and (3) enzymes to degrade and recycle the ligands. Two endogenous molecules have been identified as ligands in the ECS to date. The endocannabinoids are anandamide (arachidonoyl ethanolamide) and 2-AG (2-arachidonoyl glycerol). Two G-coupled protein receptors (GPCR) have been described as part of this system, with other putative GPC being considered. Coincidentally, the phytochemicals produced in large quantities by the Cannabis sativa L plant, and in lesser amounts by other plants, can interact with this system as ligands. These plant-based cannabinoids are termed phytocannabinoids. The precise determination of the distribution of cannabinoid receptors in animal species is an ongoing project, with the canine cannabinoid receptor distribution currently receiving the most interest in non-human animals.

Comparison of aspirin resistance in type 1 versus type 2 diabetes mellitus.

This study sought to determine the frequency of aspirin resistance in an ambulatory population of patients with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D). Platelet aggregation was assessed during the routine clinical evaluation of 203 ambulatory patients with diabetes (T1D, n = 92; T2D, n = 111) who were recommended aspirin for primary or secondary cardiovascular protection. Consecutively received laboratory samples were evaluated using the Ultegra Rapid Platelet Function Assay-ASA. Resistance to aspirin was detected in 18.7% of diabetic aspirin users, with similar rates in T1D (21.7%, p = 0.5) and T2D (16.2%, p = 0.6). Aspirin resistance was not related to age, glycohemoglobin, total cholesterol, or a history of cardiovascular disease. Female gender was a strong independent predictor of aspirin resistance in patients with T1D (p = 0.001). Platelet aggregation was correlated with high-density lipoprotein (HDL) cholesterol in the entire cohort (r = 0.21, p = 0.005) and in patients with T1D (r = 0.32, p = 0.04) or T2D (r = 0.21, p = 0.04), such that patients with low HDL cholesterol levels were more likely to be aspirin sensitive. The results suggest that aspirin can inhibit platelet aggregation in most patients with diabetes and is a reasonable first-line antiplatelet agent in patients with diabetes.

Management of thyroid incidentalomas.

The discovery of a thyroid incidentaloma warrants a systematic approach for those nodules most likely to be cancerous. An optimal management strategy for thyroid incidentalomas should be guided by four questions: (1) Does the incidentally detected thyroid nodule put the patient at risk for an adverse outcome; (2) Can those individuals with malignant thyroid nodules be identified; (3) Is the treatment of thyroid malignancy more effective in presymptomatic patients; and (4) Do the beneficial effects of presymptomatic detection and treatment in these patients justify the costs incurred Physicians caring for patients with thyroid disease should participate in data acquisition in national databases and properly randomized studies, to address the optimal management strategy in the treatment of incidentally-detected thyroid nodules.

Acute insulin secretion as a predictor of weight gain in healthy humans.

OBJECTIVE: We sought to determine the role of the acute insulin secretory response to glucose (AIRg) in predicting weight gain in normoglycemic persons with no family history of diabetes, who are at low risk for development of disease. RESEARCH METHODS AND PROCEDURES: One hundred five individuals (64 men and 41 women) who underwent measures of weight and AIRg and insulin sensitivity index (S(I)) by intravenous glucose tolerance test between 1963 and 1983 were surveyed again for weight between 1994 and 1999, with a mean follow-up of 26 +/- 4 years. RESULTS: Mean change in weight was 8 +/- 10 kg. Annualized weight change was calculated as change in kilograms divided by change in year and averaged 0.27 +/- 0.04 kg/yr. Dividing the cohort by either median AIRg or median S(I) demonstrated no association of either AIRg or S(I) with total or annualized weight gain. Subgroup analysis by ideal body weight or gender did not alter the association. Furthermore, no association between AIRg and weight gain rate was seen within insulin-sensitive or -resistant subgroups, although younger age at entry was associated with greater rates of weight gain. DISCUSSION: Our data suggest that neither AIRg nor S(I) plays a role in predicting weight gain in normoglycemic individuals with no family history of diabetes.